| DISEASE ASSOCIATIONS |
CHARACTERIZATION |
| ALOPECIA |
|
-
Stem cell apoptosis in HIV-1 alopecia.
-
University of Sao Paulo Medical School, Sao Paulo, Brazil.
|
-
J Cutan Pathol. 2006 Oct;33(10):667-71 Abstract quote
Background: Diffuse alopecia occurs in almost 7% of HIV-1-infected patients. Telogen effluvium is the main pathogenic mechanism involved. Apoptotic keratinocytes in the outer root sheath at bulge level was described as the most characteristic histopathologic finding of this kind of hair loss.
Methods: A case-control study was conducted to investigate the occurrence of apoptosis of follicular stem cells at the bulge in diffuse alopecia of HIV-1 infection. We applied a double-staining procedure to transverse scalp sections from 15 HIV-1-infected patients and 12 controls, with the monoclonal antibody anticytokeratin 19 as stem cell marker and TUNEL technique to identify apoptosis.
Results: Eighty percent of cases and 25% of controls presented at least one double-stained follicle. The proportion of positive follicles per section was 48% (+/-7%) for cases and 26% (+/-13%) for controls.
Conclusion: Our study demonstrated that diffuse alopecia related to HIV-1 infection represents a hair cycle disturbance and that part of the follicular stem cell population become apoptotic in a higher proportion than normal subjects. We found no cytotoxic folliculitis. Owing to its cell-cycle interaction and caspase-induction capacities, we propose HIV-1 viral protein R as a possible follicular stem cell apoptosis inductor.
|
| CANCER-GENERAL |
|
|
Non-acquired immunodeficiency syndrome-defining malignancies in patients
infected with human immunodeficiency virus.
Demopoulos BP, Vamvakas E, Ehrlich JE, Demopoulos R.
Weill Medical College of Cornell University, New York, NY,
USA.
|
Arch Pathol Lab Med 2003 May;127(5):589-92 Abstract quote
CONTEXT: Non-acquired immunodeficiency syndrome (AIDS)-defining malignancies
that occur in patients infected with human immunodeficiency virus (HIV)
and the demographics and pathologic features associated with these malignancies
have not been completely defined.
OBJECTIVE: This study describes the age of onset of malignant disease
in patients seropositive for HIV and in control patients presumed to
be negative for HIV, but with the same primary site. We compare the
demographics and histopathology for both groups.
DESIGN: From 1993 to 1997, 57 cases involving HIV-positive patients
with malignancies from 16 primary sites were recorded in the Cancer
Registry files at Bellevue Hospital; 519 cases involving patients negative
for HIV were recorded during this same period. We compared the age at
diagnosis, sex, race, tumor histology, stage, and grade between these
2 groups.
RESULTS: The average age of HIV-positive patients was 47.6 years, compared
with 60.3 years in the control group (P <.001). When the 16 cancer
sites were compared individually, HIV-positive patients were significantly
younger at onset of lung (HIV-positive patients/control group) (19/245),
skin (11/77), penile (3/5), laryngeal (3/18), tongue (5/16), and colorectal
(2/38) carcinomas. Patients infected with HIV had a more frequent history
of smoking (41/328; P =.04) and illicit drug use (30/49; P <.001).
The HIV-positive patients also were found to have a lower clinical stage
of disease, compared with controls, largely due to the higher prevalence
of stage 0 tumors (13/46; P =.01).
CONCLUSIONS: The finding of younger age at diagnosis in HIV-positive
compared to presumed HIV-negative patients may be related in part to
earlier detection, as well as preexisting immunosuppression. The specific
sites for which a significant difference in age between the HIV-positive
and control cases was observed may be related to the mechanisms of immunosurveillance
in parts of the body that have ready access to the outside environment.
Knowledge of younger age of onset for these malignancies should prompt
closer physical examination of these sites by clinicians. |
| Risk of cancer in children with AIDS. AIDS-Cancer
Match Registry Study Group.
Biggar RJ, Frisch M, Goedert JJ.
VEB/NCI, 6120 Executive Blvd, Room 8014, Bethesda, MD 20852. |
JAMA 2000 Jul 12;284(2):205-9 Abstract quote
CONTEXT: Population-based data on cancers associated with acquired
immunodeficiency syndrome (AIDS) in children are lacking.
OBJECTIVE: To determine risk of pediatric AIDS-associated cancers.
DESIGN, SETTING, AND PARTICIPANTS: Using records from 11 locations
in the United States for varying periods between 1978 and 1996, we linked
data for children aged 14 years and younger at AIDS diagnosis to local
cancer registry data.
MAIN OUTCOME MEASURES: Cancer frequency and, in the 2-year post-AIDS
onset period, cancer incidence and relative risk (RR; measured as standardized
incidence ratio), by cancer type.
RESULTS: Among 4954 children with AIDS, 124 (2.5%) were identified
as having cancer before, at, or after AIDS onset, including 100 cases
of non-Hodgkin lymphoma (NHL), 8 of Kaposi sarcoma (KS), 4 of leiomyosarcoma,
and 2 of Hodgkin disease; there were 10 other or unspecified cancers.
Expected numbers for all cancers identified in the study sample, based
on population rates (using area-specific registry data), were less than
1. In the first 2 years after AIDS diagnosis (5485 person-years), NHL
incidence was 510 per 100,000 person-years (RR, 651; 95% confidence
interval [CI], 432-941). Median time for developing NHL after AIDS diagnosis
was 14 months (range, 3-107 months). The most common type of NHL was
Burkitt lymphoma. However, the risk of primary brain lymphoma (91 per
100,000 person-years) was especially high (RR, 7143; 95% CI, 2321-16,692),
and 4 cases were diagnosed more than 2 years (range, 37-98 months) after
AIDS onset. Leiomyosarcomas also tended to occur several years after
AIDS onset, with 3 of the 4 cases occurring 33 to 76 months after AIDS
diagnosis, whereas KS was reported only at or within 2 years of AIDS
diagnosis. Hodgkin disease risk was also significantly increased (RR,
62; 95% CI, 2-342).
CONCLUSIONS: The spectrum of AIDS-associated pediatric cancers resembled
that seen in adults, with the addition of leiomyosarcoma. Both primary
brain lymphomas and leiomyosarcomas tended to occur in children surviving
several years after AIDS onset. Because the expected numbers of these
cancers in this population were less than 1 and because of the small
numbers of some types of observed cancers, the RR estimates are imprecise
and caution is warranted in their interpretation |
| Prevalence and predictors of skin disease in the
Women's Interagency HIV Study (WIHS)
Paradi Mirmirani, etal. |
J Am Acad Dermatol 2001;44:785-8 Abstract quote
Objective: We attempted to determine the prevalence and predictors
of skin disease in a cohort of women with and at risk for HIV infection.
Methods: We analyzed baseline data from a multicenter longitudinal
study of HIV infection in women.
Results: A total of 2018 HIV-infected women and 557 HIV-uninfected
women were included in this analysis. Skin abnormalities were reported
more frequently among HIV-infected than uninfected women (63% vs 44%,
respectively; odds ratio [OR] 2.10; 95% confidence interval [95% CI],
1.74-2.54). Infected women were also more likely to have more than 2
skin diagnoses (OR, 3.27; 95% CI, 1.31-8.16). Folliculitis, seborrheic
dermatitis, herpes zoster, and onychomycosis were more common among
HIV-infected women (P < .05). Independent predictors of abnormal findings
on skin examination in the infected women were African American race
(OR, 1.38; 95% CI, 1.07-1.77), injection drug use (OR, 2.74; 95% CI,
2.11-3.57), CD4+ count less than 50 (OR, 1.68; 95% CI, 1.17-2.42), and
high viral loads (100,000-499,999 = OR, 1.77; 95% CI, 1.32-2.37; >499,999
= OR, 2.15; 95% CI, 1.42-3.27).
Conclusion: HIV infection was associated with a greater number of skin
abnormalities and with specific dermatologic diagnoses. Skin abnormalities
were also more common among women with CD4+ cell depletion or higher
viral load. |
| ALCOHOLISM |
|
| HIV and alcohol use: Consequences of comorbidity
Bean P. |
Am Clin Lab 2001;20:13-16
Poor compliance with medications
Alcohol upregulates CXCR4 chemokine receptor leading to enhanced HIV replication
in quiescent lymphocytes
Alcohol reactivates HIV-1 infected latent peripheral blood lymphocytes
and increases viral replication
Alcohol inhibits thymidine kinase activity essential for activation of
AZT |
| LYMPHOMA |
|
|
AIDS-related non-Hodgkin's lymphomas: From pathology and molecular pathogenesis
to treatment.
Carbone A.
Division of Pathology and Scientific Direction, Centro di Riferimento
Oncologico-IRCCS, National Cancer Institute, Aviano, Italy. |
Hum Pathol 2002 Apr;33(4):392-404 Abstract quote
In the highly active antiretroviral therapy (HAART) era, AIDS-related
non-Hodgkin's lymphomas (AIDS-NHL) and their treatment still represent
an open issue, because HAART may not be sufficient to prevent the development
of NHL. The present spectrum of AIDS-NHL includes systemic lymphomas,
primary central nervous system lymphomas, and 2 rare entities, primary
effusion lymphomas (PEL) and plasmablastic lymphomas of the oral cavity.
The vast majority of systemic AIDS-NHL belongs to 3 high-grade B-cell
lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and
large-cell lymphoma (LCL). The pathologic heterogeneity of AIDS-NHL
is correlated with the heterogeneity of the molecular lesions associated
with these lymphomas. The molecular lesions associated with AIDS-BL
involve activation of c-MYC inactivation of p53, and infection by Epstein-Barr
virus (EBV). EBV infection occurs in 40% of LCL cases and in 90% of
IBL cases. Rearrangements of BCL-6 are detected in 20% of AIDS-LCL cases.
In the presence of EBV infection, BCL-6 expressing AIDS-LCL fails to
express the latent membrane protein 1 (LMP1) antigen. Conversely, AIDS-IBL
are characterized by absent BCL-6 expression, absence of BCL-6 rearrangements,
and frequent expression of LMP1. Consistently, the molecular pathways
of viral infection and lesions of cancer-related genes associated with
AIDS-NHL vary substantially in different clinicopathologic categories
of the disease. The marked degree of biologic heterogeneity of AIDS-NHL
is highlighted by their histogenetic differences, because AIDS-NHL are
related to distinct B cell subsets (ie, germinal center [GC] or post-GC
B cells). The phenotypic pattern of AIDS-BL and systemic AIDS-LCL closely
reflects B cells residing in the GC, namely centroblasts and centrocytes.
Conversely, the phenotype of AIDS-IBL, either systemic or localized
primarily to the central nervous system, and AIDS-PEL reflects post-GC
B cells in all cases.
New information on the molecular and virologic pathogenesis of AIDS-NHL
may serve as a point of attack for pathogenic-driven therapies. Moreover,
a greater knowledge of other biologic features of these tumors may help
investigators identify new potential targets for "intelligent"
therapies. |
| MELANOMA |
|
|
Altered Clinical Course of Malignant Melanoma in HIV-Positive Patients.
Rodrigues LK, Klencke BJ, Vin-Christian K, Berger TG, Crawford RI,
Miller JR 3rd, Ferreira CM, Nosrati M, Kashani-Sabet M.
University of California, San Francisco, Melanoma Center, UCSF Comprehensive
Cancer Center, 1600 Divisadero St, San Francisco, CA 94115.
|
Arch Dermatol 2002 Jun;138(6):765-70 Abstract quote
OBJECTIVE: To determine whether the natural history of melanoma is
different in patients who test positive for human immunodeficiency virus
(HIV) compared with matched control subjects.
DESIGN: Retrospective cohort analysis.
SETTING: Ambulatory care at 2 university-affiliated medical centers.
PATIENTS: Each HIV-positive melanoma patient (n = 17) was randomly matched
with 2 HIV-negative patients (HIV status unknown, but without risk factors
for HIV) based on the melanoma subtype, tumor thickness, Clark level,
tumor location, and sex and age of the patient.
MAIN OUTCOME MEASURES: Disease-free survival and overall survival of
HIV-positive and HIV-negative melanoma patients were compared using
a matched-pairs analysis. CD4 cell counts were recorded at the time
of melanoma diagnosis and disease recurrence.
RESULTS: Melanoma patients who were HIV positive had a significantly
shorter disease-free survival (P =.03) and overall survival (P =.045)
compared with HIV-negative melanoma patients by matched-pairs analysis.
There was an inverse relationship between CD4 cell counts and time to
first melanoma recurrence.
CONCLUSIONS: The natural history of malignant melanoma in HIV-positive
patients is more aggressive compared with matched HIV-negative melanoma
patients. Altered immune response and comorbid disease may play a role
in the poor clinical outcome of HIV-positive patients. These findings
have important implications in the management of melanoma in the setting
of HIV disease. |
| MERKEL CELL CARCINOMA |
|
|
Merkel cell carcinoma and HIV infection.
Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. |
Lancet 2002 Feb 9;359(9305):497-8 Abstract quote
Merkel cell carcinoma (MCC) is a rare skin cancer that occurs more
frequently after organ transplantation or B-cell malignancy, conditions
of suppressed or disordered immunity.
To assess further whether immune suppression increases MCC risk, we
studied its occurrence in a cohort of 309365 individuals with acquired
immunodeficiency syndrome (AIDS) by using linked AIDS and cancer registries.
We identified six cases of MCC, corresponding to a relative risk of
13.4 (95% CI 4.9-29.1) compared with the general population. These results
suggest that immune suppression induced by the human immunodeficiency
virus increases MCC risk. |
| PATHOGENESIS |
CHARACTERIZATION |
| Human immunodeficiency virus |
Lentivirus, subgroup retrovirus
This virus mutates frequently and a single patient may develop many
mutant strains of the virus
Median time between infection and development of AIDS is 10 years
Currently divided into groups based upon genetic diversity:
|
|
Group M
|
Ten subtypes (A-J)
Majority of infected cases
Subtype B is most prevalent strain in US and Western Europe
|
|
Group O
|
More severe mechanism attacking 2 additional T cell types |
|
Group N
|
Isolated from female patient in Cameroon and may represent
a cross between Group M and the simian virus (SIV) |
| Viral infectivity |
All determined by the viral titer, viral structure, and the replicating
energy and pathogenicity of the virus
Influenced by both the donor and recipient
|
| Virus structure |
11 identified genes consisting of 2 identical RNA strands with 2 core
proteins, p18 and p24
Spiked envelope surrounding the HIV capsid:
Gp 120 is the envelope glycoprotein, located on the tips of the spikes
Glycoprotein stalk gp41 anchors gp120 to the viral envelope
|
| Acute Infection |
M-tropic strains target macrophages
T-tropic strains infect T-lymphocytes
HIV infects macrophages at the CD4 site but this infection is dependent
upon chemokine coreceptors (CCR5) which determine whether the virus
enters the cell or not
First step in the progression of the disease is thought to be binding
of the viral gp120 to the CD4 receptor on the T-helper lymphocytes
HIV binding leads to fusion to the host cell membrane with passage,
utilizing the fusin protein
Once in the cell, the virus sheds its envelope releasing the viral
RNA and the viral enzyme reverse transcriptase which creates a DNA transcript
Viral DNA is transported into the nucleus of the host cell where the
viral enzyme integrase integrates the HIV DNA into the host cell's DNA
Once integrated, a DNA polymerase speeds up DNA replication producing
large, non-functional polypeptide chains (polyproteins)
Chains are packaged to form immature virions and HIV-1 protease cleaves
the polyproteins into smaller, functional proteins, maturing the virion
into infectious virions which eventually bud from the cell
Protease enzyme also creates a multitude of viral regulatory and strctural
proteins
|
| Chronic Infection |
After seroconversion, most people remain asymptomatic for many years
High rates of viral replication is occurring within the lymph nodes
during this period and may be accompanied by a high viral load within
the plasma even if the peripheral blood cell viral count is low-this
is because only 2% of the total T-cell population is found in the peripheral
blood
With depletion of the CD4 T-cells, HIV rises in the peripheral blood
and clinical symptoms begin to appear
|
| ANTIGEN PRESENTING CELLS |
|
|
In Vivo Identification of Langerhans and Related Dendritic Cells
Infected with HIV-1 Subtype E in Vaginal Mucosa of Asymptomatic Patients
Lertlakana Bhoopat, M.D., Lukana Eiangleng, M.T., Sungwal Rugpao,
M.D., Sarah S. Frankel, M.D., Drew Weissman, M.D., Ph.D., Suree Lekawanvijit,
M.D., Supinda Petchjom, M.D., Paul Thorner, M.D., Ph.D. and Tanin Bhoopat,
M.D.
Departments of Pathology (LB, LE, SL, SP), Obstetrics and Gynecology
(SR), and Forensic Medicine (TB), Faculty of Medicine, Chiang Mai University,
Chiang Mai, Thailand; Department of Infectious and Parasitic Disease
Pathology (SSF), Armed Forces Institute of Pathology, Washington DC;
Division of Infectious Diseases (DW), University of Pennsylvania, Philadelphia,
Pennsylvania; Division of Pathology (PT), Hospital for Sick Children,
and Department of Laboratory Medicine and Pathobiology (PT), University
of Toronto, Toronto, Canada
|
Mod Pathol 2001;14:1263-1269 Abstract quote
In Thailand, the predominant HIV subtype is E, rather than Subtype
B as in North America and Europe, and the predominant mode of transmission
is heterosexual contact. Subtype E has the ability to replicate in vitro
in Langerhans cells.
We hypothesized that this cell type might constitute a reservoir for
the HIV virus in vaginal mucosa of asymptomatic carriers. To examine
this hypothesis, we compared vaginal tissue histology in HIV-1–seropositive
cases with seronegative cases and determined the immunophenotype of
HIV-1–infected cells, their numbers, and their distribution in vaginal
mucosa.
Vaginal biopsies were performed at four different sites from six asymptomatic
HIV-1 Subtype E–infected persons and from six seronegative cases at
necropsy and examined histologically. Immunophenotyping was performed
using immunoperoxidase for Gag p24 HIV, CD3, CD20, CD68, CD1a, S-100
and p55 antigens and by double labeling, combining immunoperoxidase
with alkaline phosphatase using pairs of the above antigens.
Twenty of twenty-four vaginal biopsies (83.3%) from HIV-seropositive
cases showed definite inflammation compared to five of twenty-four vaginal
necropsies (20.8%) from HIV-seronegative cases. One third of HIV-seropositive
biopsies (8/24) demonstrated p24-positive cells in the epithelium, whereas
three-fourths (18/24) of the biopsies revealed p24-positive cells in
the lamina propria. All seropositive patients showed positive cells
in at least one biopsy, but not all biopsies contained positive cells.
Infected cells were more frequently observed at sites of greater inflammation.
The dendritic cell count in HIV-seropositive vaginal epithelium was
significantly higher than that observed in the seronegative cases (P
= .004). The majority of p24-positive cells in the vaginal epithelium
were Langerhans cells (CD1a+/S-100+), whereas in the lamina propria,
about half of p24-positive cells were Langerhans-related dendritic cells
(p55+ and S-100+) and half were T lymphocytes.
In conclusion, the increased propensity for heterosexual transmission
of Subtype E may be related to vaginal inflammation, leading to the
accumulation of Langerhans cells and related dendritic cells which,
once infected with HIV, can act as a reservoir for further virus transmission.
|
| CKR (CHEMOKINE RECEPTOR GENE) |
|
|
Resistance to HIV-1 infection in caucasian individuals bearing mutant
alleles of the CCR-5 chemokine receptor gene.
Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM,
Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G,
Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ,
Collman RG, Doms RW, Vassart G, Parmentier M.
IRIBHN and Services de Genetique Medicale, Virologie and Immunodeficiences,
Universite Libre de Bruxelles, Belgium.
|
Nature 1996 Aug 22;382(6593):722-5 Abstract quote
HIV-1 and related viruses require co-receptors, in addition to CD4,
to infect target cells. The chemokine receptor CCR-5 (ref.1) was recently
demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1
strains, and the orphan receptor LESTR (also called fusin) allows infection
by strains adapted for growth in transformed T-cell lines (T-tropic
strains).
Here we show that a mutant allele of CCR-5 is present at a high frequency
in caucasian populations (allele frequency, 0.092), but is absent in
black populations from Western and Central Africa and Japanese populations.
A 32-base-pair deletion within the coding region results in a frame
shift, and generates a non-functional receptor that does not support
membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains.
In a cohort of HIV-1 infected caucasian subjects, no individual homozygous
for the mutation was found, and the frequency of heterozygotes was 35%
lower than in the general population. White blood cells from an individual
homozygous for the null allele were found to be highly resistant to
infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major
co-receptor for primary HIV-1 strains.
The lower frequency of heterozygotes in seropositive patients may
indicate partial resistance.
|
| Genetic restriction of HIV-1 infection and progression
to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth
and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia
Cohort Study, San Francisco City Cohort, ALIVE Study.
Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets
R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S,
Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ.
Laboratory of Genomic Diversity, National Cancer Institute (NCI),
Frederick, MD 21702-1201, USA..
|
Science 1996 Sep 27;273(5283):1856-62 Abstract quote
The chemokine receptor 5 (CKR5) protein serves as a secondary receptor
on CD4(+) T lymphocytes for certain strains of human immunodeficiency
virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome
3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified
that is present at a frequency of approximately0.10 in the Caucasian
population of the United States.
An examination of 1955 patients included among six well-characterized
acquired immunodeficiency syndrome (AIDS) cohort studies revealed that
17 deletion homozygotes occurred exclusively among 612 exposed HIV-1
antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected
individuals. The frequency of CKR5 deletion heterozygotes was significantly
elevated in groups of individuals that had survived HIV-1 infection
for more than 10 years, and, in some risk groups, twice as frequent
as their occurrence in rapid progressors to AIDS.
Survival analysis clearly shows that disease progression is slower
in CKR5 deletion heterozygotes than in individuals homozygous for the
normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction
gene against HIV-1 infection and may exert a dominant phenotype of delaying
progression to AIDS among infected individuals.
|
|
The role of a mutant CCR5 allele in HIV-1 transmission and disease
progression.
Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang
S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon
E, Landau NR, Phair J, Ho DD, Koup RA.
Aaron Diamond AIDS Research Center, New York, New York, USA.
|
Nat Med 1996 Nov;2(11):1240-3 Abstract quote
A 32-nucleotide deletion (delta 32) within the beta-chemokine receptor
5 (CCR5) gene has been described in subjects who remain uninfected despite
extensive exposure to HIV-1. This allele was found to be common in the
Caucasian population with a frequency of 0.0808, but was not found in
people of African or Asian ancestry.
To determine its role in HIV-1 transmission and disease progression,
we analyzed the CCRS genotype of 1252 homosexual men enrolled in the
Chicago component of the Multicenter AIDS Cohort Study (MACS). No infected
participant was found to be homozygous for the delta 32 allele, whereas
3.6% of at-risk but uninfected Caucasian participants were homozygous,
showing the highly protective role of this genotype against sexual acquisition
of HIV-1. No evidence was found to suggest that heterozygotes were protected
against HIV-1 infection, but a limited protective role against disease
progression was noted.
The delta 32 allele of CCR5 is therefore an important host factor in
HIV-1 transmission and pathogenesis.
|
|
Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection
and disease progression. Hemophilia Growth and Development Study (HGDS),
Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort
Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.
Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA,
Goedert JJ, O'Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff
E, Vlahov D, Hoots K, Hilgartner MW, O'Brien SJ.
Science Applications International Corp. Frederick, National Cancer
Institute, Frederick, MD 21702-1201, USA.
|
Science 1997 Aug 15;277(5328):959-65 Abstract quote
The critical role of chemokine receptors (CCR5 and CXCR4) in human
immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted
a search for polymorphisms in other chemokine receptor genes that mediate
HIV-1 disease progression.
A mutation (CCR2-64I) within the first transmembrane region of the
CCR2 chemokine and HIV-1 receptor gene is described that occurred at
an allele frequency of 10 to 15 percent among Caucasians and African
Americans. Genetic association analysis of five acquired immunodeficiency
syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I
exerts no influence on the incidence of HIV-1 infection, HIV-1-infected
individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years
later than individuals homozygous for the common allele. Because CCR2-64I
occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent
effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I
were determined.
An estimated 38 to 45 percent of AIDS patients whose disease progresses
rapidly (less than 3 years until onset of AIDS symptoms after HIV-1
exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype,
whereas the survival of 28 to 29 percent of long-term survivors, who
avoid AIDS for 16 years or more, can be explained by a mutant genotype
for CCR2 or CCR5.
|
|
Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene
variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS),
Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort
Study (MHCS), San Francisco City Cohort (SFCC)
Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean
M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert
JJ, O'Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts
E, Vlahov D, Phair J, O'Brien SJ.
Science Applications International Corporation (SAIC), National
Cancer Institute, Frederick, MD 21702, USA.
|
Science 1998 Jan 16;279(5349):389-93 Abstract quote
Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a
coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency
virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified
in an evolutionarily conserved segment of the 3' untranslated region
of the SDF-1 structural gene transcript.
In the homozygous state, SDF1-3'A/3'A delays the onset of acquired
immunodeficiency syndrome (AIDS), according to a genetic association
analysis of 2857 patients enrolled in five AIDS cohort studies.
The recessive protective effect of SDF1-3'A was increasingly pronounced
in individuals infected with HIV-1 for longer periods, was twice as
strong as the dominant genetic restriction of AIDS conferred by CCR5
and CCR2 chemokine receptor variants in these populations, and was complementary
with these mutations in delaying the onset of AIDS.
|
|
Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors)
in resistance to HIV-1 infection and AIDS development among intravenous
drug users.
Alvarez V, Lopez-Larrea C, Coto E.
Laboratorio de Genetica Molecular (Instituto Reina Sofia de Investigaciones
Nefrologicas), Hospital Central de Asturias, Oviedo, Spain.
|
Hum Genet 1998 Apr;102(4):483-6 Abstract quote
We analysed a group of Spanish intravenous drug users and controls
to determine the role of mutations at the chemokine receptor-5/HIV-1
cofactor (CCR5), previously implicated in resistance to HIV-1 infection,
and CXCR4 genes in susceptibility to HIV-1 infection.
The complete coding sequence of both genes was amplified by the polymerase
chain reaction from genomic DNA of 50 seropositive slow progressors
and 10 long-term non-progressors, and analysed by the single-strand
conformation polymorphism technique in a search for mutations. No mutation
in CXCR4 was found, and delta ccr5 was the only mutation identified
at the CCR5 gene.
We genotyped (delta ccr5 allele) 150 HIV-1+ intravenous drug users
and 250 healthy controls from the same population (Asturias, Northern
Spain). Patients were divided into rapid progressors, presenting an
event indicating progression to the acquired immunodeficiency syndrome
(AIDS) in the 2 years after infection (100 patients), and slow progressors,
remaining asymptomatic for 2-10 years (50 patients). The frequencies
of the delta ccr5 allele were 0.105 and 0.040 in controls and HIV-1+
patients, respectively. Eighteen per cent of the controls (45/250) and
8% (12/150) of the patients carried the delta ccr-5 allele (P=0.013).
The frequency of delta ccr5 carriers among rapid and slow disease progressors
was 3 and 15%, respectively. A highly significant difference was found
between rapid progressors and controls (P=0.0014). No patient (0/150)
was delta ccr5 homozygous compared with 1% among controls.
Thus, the delta ccr5 allele (the only CCR5 mutation found in our HIV-1
patients) was rare among seropositive intravenous drug users, suggesting
that the absence of this mutation confers an advantage to the virus
when infecting cells in vivo. In addition, patients carrying the delta
ccr5 allele tend to show a slow progression towards HIV-1-related disease,
remaining asymptomatic for longer periods of time.
|
|
CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter
AIDS Cohort Study (MACS).
McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF,
Murphy PM.
Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
|
Lancet 1998 Sep 12;352(9131):866-70 Abstract quote
BACKGROUND: The rate of progression to AIDS varies among individuals
infected with HIV-1. Factors responsible include two inherited human
alleles, CCR5 delta32 and CCR2-641, which alter the protein-coding regions
for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested
the hypothesis that polymorphisms of the CCR5 promoter might affect
the rate of progression of HIV-1 infected people to AIDS.
METHODS: We used directed heteroduplex analysis to identify polymorphism
in the CCR5 promoter. Promoter-variants were compared in vitro with
a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping
HIV-1 seroconvertors discordant at polymorphous loci.
FINDINGS: An A/G polymorphism was identified at basepair 59029 (Genbank
U95626) in the CCR5 promoter. Both promoter alleles were common (43-68%
allelic frequency for 59029-A depending on race). When in-vitro promoter
activity was measured, 59029-G had 45% lower activity than 59029-A (p=0.05).
In a cohort of HIV-1 seroconvertors lacking both CCR5 delta32 and CCR2-641,
59029-G/G individuals progressed to AIDS on average 3.8 years more slowly
than 59029-A/A individuals (p=0.004). 59029-G/A discordance did not
correlate with discordant rates of infection.
INTERPRETATION: Our results are consistent with the hypothesis that
CCR5 is important in HIV-1 pathogenesis. CCR5 59029-G/G appears to be
protective relative to CCR5 59029-A/A, and about twice as protective
relative to CCR5 delta32 or CCR2-641. This effect may be the result
of reduced CCR5 mRNA production. These results identify the first site
in the CCR5 promoter that may be a useful target for treatment of HIV-1
infection.
|
|
Impact of heterozygosity for the chemokine receptor CCR5 32-bp-deleted
allele on plasma virus load and CD4 T lymphocytes in perinatally human
immunodeficiency virus-infected children at 8 years of age.
Buseyne F, Janvier G, Teglas JP, Ivanoff S, Burgard M, Bui E, Mayaux
MJ, Blanche S, Rouzioux C, Riviere Y.
Unite de Virologie et Immunologie Cellulaire, Institut Pasteur,
Paris, France.
|
J Infect Dis 1998 Oct;178(4):1019-23 Abstract quote
The CCR5 gene encodes one of the major human immunodeficiency virus
type 1 (HIV-1) coreceptors. A 32-bp deletion in this gene (delta ccr5)
is associated with relative resistance to disease progression in heterozygous
HIV-1-infected persons.
The effect of this mutation on virologic and immunologic parameters
was determined in a cohort of 45 perinatally HIV-1-infected children
prospectively followed after 5 years of age. At a median age of 8.3
years, heterozygous children had significantly lower virus load than
homozygous children (median, 3.3 vs. 4.1 log copies/mL, P < .009)
and higher percentages of CD4 T cells (median, 26% vs. 17%, P < .07).
However, there was no discernible influence of the CCR5 genotype on
the percentages of CD8 T cells (P < .27) or on HIV-specific cytotoxic
T lymphocyte activities (P < .65). There was a trend for lower rates
of progression to AIDS (CDC stage C) in heterozygous children.
These data confirm a major role for the CCR5 coreceptor in HIV-1 pathogenesis
in children.
|
|
A 32-bp deletion within the CCR5 locus protects against transmission
of parenterally acquired human immunodeficiency virus but does not affect
progression to AIDS-defining illness.
Wilkinson DA, Operskalski EA, Busch MP, Mosley JW, Koup RA.
Department of Medicine, University of Texas Southwestern Medical
Center, Dallas 75235-9113, USA.
|
J Infect Dis 1998 Oct;178(4):1163-6 Abstract quote
The beta-chemokine receptor CCR5 is required as a coreceptor by non-syncytium-inducing
(NSI) strains of human immunodeficiency virus type 1 (HIV-1). NSI viruses
predominate early during an infection and are thought to be important
for the transmission of HIV-1. The importance of CCR5 during parenteral
transmission of HIV-1 was investigated.
The distribution of the homozygous deleted CCR5 genotype among 566
exposed persons with hemophilia and 97 exposed transfusion recipients
indicated that the lack of CCR5 expression protected persons from infection.
This suggests that the initial predominance of NSI viruses during an
infection does not result from limited availability of CXCR4-expressing
cells within the mucosa but rather implies a more fundamental requisite
for CCR5-expressing cells early during an infection regardless of the
route of transmission.
In addition, no difference in the rate of progression to AIDS (CDC
1987 definition) of infected heterozygous compared with homozygous wild
type subjects was observed.
|
|
Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in
AIDS progression.
Hendel H, Henon N, Lebuanec H, Lachgar A, Poncelet H, Caillat-Zucman
S, Winkler CA, Smith MW, Kenefic L, O'Brien S, Lu W, Andrieu JM, Zagury
D, Schachter F, Rappaport J, Zagury JF.
Laboratoire de Physiologie Cellulaire, Universite Pierre et Marie
Curie, Paris, France.
|
J Acquir Immune Defic Syndr Hum Retrovirol 1998 Dec 1;19(4):381-6
Abstract quote
The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents
200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor
(Fastprog) HIV-1-infected patients.
Using this unique assembly, we performed genetic studies on three recently
discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown
to slow the rate of disease progression. The increased prevalence of
mutant alleles among Slowprogs from the GRIV cohort was significant
for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = . 12),
emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor.
However, the prevalence of the CCR2 mutant allele (64I) was significantly
increased among Slowprogs homozygous for wild-type CCR5 compared with
Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes
was also increased among Slowprogs homozygous for wild-type CCR5 compared
with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations
are overshadowed by the protective effects of the CCR5 deletion. Predictive
biologic markers such as CD4 cell counts or viral load in the Slowprog
population did not show significant differences between Slowprog groups
with wild-type or mutant alleles for the three genes.
Thus, our data suggest that the effects of these genes are exerted
earlier in infection and no longer evident in the Slowprog of the GRIV
cohort whose average duration of HIV infection is 12 years. We conclude
that these genes, whose products serve as viral coreceptors or their
ligands, may play a role early in infection and delay the onset of disease.
However, among Slowprogs, whose duration of infection is >8 years,
they are no longer influential for maintenance of their longterm nonprogression
status. Other genetic determinants may be responsible for late protective
effects.
|
|
Genetic acceleration of AIDS progression by a promoter variant of CCR5.
Martin MP, Dean M, Smith MW, Winkler C, Gerrard B, Michael NL, Lee
B, Doms RW, Margolick J, Buchbinder S, Goedert JJ, O'Brien TR, Hilgartner
MW, Vlahov D, O'Brien SJ, Carrington M.
Science Applications International Corporation (SAIC), National
Cancer Institute, Frederick MD 21702, USA.
|
Science 1998 Dec 4;282(5395):1907-11 Abstract quote
The CCR5 gene encodes a cell surface chemokine receptor molecule that
serves as the principal coreceptor, with CD4, for macrophage-tropic
(R5) strains of human immunodeficiency virus-type 1 (HIV-1).
Genetic association analysis of five cohorts of people with acquired
immunodeficiency syndrome (AIDS) revealed that infected individuals
homozygous for a multisite haplotype of the CCR5 regulatory region containing
the promoter allele, CCR5P1, progress to AIDS more rapidly than those
with other CCR5 promoter genotypes, particularly in the early years
after infection. Composite genetic epidemiologic analyses of genotypes
bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct
regulatory influences for each gene on AIDS progression. An estimated
10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1
infection do so because they are homozygous for CCR5P1/P1, and 7 to
13 percent of all people carry this susceptible genotype.
The cumulative and interactive influence of these AIDS restriction
genes illustrates the multigenic nature of host factors limiting AIDS
disease progression.
|
|
Combined genotypes of CCR5, CCR2, SDF1, and HLA genes can predict the
long-term nonprogressor status in human immunodeficiency virus-1-infected
individuals.
Magierowska M, Theodorou I, Debre P, Sanson F, Autran B, Riviere
Y, Charron D, Costagliola D.
Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR CNRS 7627,
Hopital Pitie-Salpetriere, Paris, France.
|
Blood 1999 Feb 1;93(3):936-41 Abstract quote
Human immunodeficiency virus (HIV)-1-infected long-term nonprogressors
(LT-NP) represent less than 5% of HIV-1-infected patients.
In this work, we tried to understand whether combined genotypes of
CCR5-triangle up32, CCR2-64I, SDF1-3'A and HLA alleles can predict the
LT-NP status. Among the chemokine receptor genotypes, only the frequency
of the CCR5-triangle up32 allele was significantly higher in LT-NP compared
with the group of standard progressors. The predominant HLA alleles
in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7.
A combination of both HLA and chemokine receptor genotypes integrated
in a multivariate logistic regression model showed that if a subject
is heterozygous for CCR5-triangle up32 and homozygous for SDF1 wild
type, his odds of being LT-NP are increased by 16-fold, by 47-fold when
a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also
if at least three of the following alleles are present: HLA-A3, HLA-B14,
HLA-B17, HLA-DR7. This model allowed a correct classification of 70%
of LT-NPs and 81% of progressors, suggesting that the host's genetic
background plays an important role in the evolution of HIV-1.
The chemokine receptor and chemokine genes along with the HLA genotype
can serve as predictors of HIV-1 outcome for classification of HIV-1-infected
subjects as LT-NPs or progressors.
|
|
Persistent CCR5 utilization and enhanced macrophage tropism by primary
blood human immunodeficiency virus type 1 isolates from advanced stages
of disease and comparison to tissue-derived isolates.
Li S, Juarez J, Alali M, Dwyer D, Collman R, Cunningham A, Naif
HM.
Centre for Virus Research, Westmead Millennium Institute, National
Centre for HIV Virology Research, Westmead, NSW 2145, Australia.
|
J Virol 1999 Dec;73(12):9741-55 Abstract quote
Viral phenotype, tropism, coreceptor usage, and envelope gene diversity
were examined in blood isolates collected from 27 individuals at different
stages of human immunodeficiency virus type 1 (HIV-1) disease and tissue
derived isolates from 10 individuals with AIDS.
The majority (89%) of blood and all tissue HIV-1 isolates from all
stages of infection were non-syncytium inducing and macrophage (M) tropic.
Tropism and productive infection by HIV isolates in both monocytes and
monocyte-derived macrophages (MDM) increased in advanced disease (HIV
tropism for monocytes, 1 of 6 from categories I and II versus 11 of
21 [P = 0.05] from category IV and II [CD4 < 250]; and high-level
replication in MDM, 1 of 6 from categories I and II versus 16 of 21
from categories IV and II [P = 0. 015]). There was a high level of replication
of blood and tissue isolates in T lymphocytes without restriction at
any stage.
Overall, the level of replication in MDM was 5- to 10-fold greater
than in monocytes, with restriction in the latter occurring mainly at
entry and later stages of replication. Only three blood isolates were
identified as syncytium inducing, and all had a dualtropic phenotype.
There was a significant increase of HIV envelope gene diversity, as
shown by a heteroduplex mobility assay, in advanced disease; this may
partly underlie the increase of HIV replication in MDM. Unlike blood
isolates (even those from patients with advanced disease), tissue isolates
displayed greater similarities (90%) in productive infection between
MDM and monocytes. The majority (87%) of all isolates, including those
from patients with advanced disease, used CCR5, and only 5 of 37 isolates
showed expanded coreceptor usage.
These results indicate that in the late stage of disease with increasing
viral load and diversity, CCR5 utilization and M-tropism persist in
blood and tissue and the replicative ability in macrophages increases.
This suggests that these characteristics are advantageous to HIV and
are important to disease progression.
|
|
The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV
disease progression in individuals with haemophilia.
Pasi KJ, Sabin CA, Jenkins PV, Devereux HL, Ononye C, Lee CA.
Department of Haematology, Katharine Dormandy Haemophilia Centre,
Royal Free and University College Medical School, London, UK.
|
Br J Haematol 2000 Oct;111(1):136-42 Abstract quote
The chemokine receptor CCR5 is an important co-receptor for cell fusion.
A 32-bp deletion of the CCR5 gene, leading to complete absence of functional
CCR5 expression, has been associated with resistance to human immunodeficiency
virus (HIV) infection in homozygotes and slower HIV disease progression
in heterozygotes.
The objectives of this study were to assess the effects of this 32-bp
deletion on transmission of HIV infection and on HIV disease progression
in haemophilic individuals. Six HIV-negative patients from our centre,
known to have been exposed to infectious factor VIII concentrates, have
been analysed. Three of these patients possess the CCR5 32-bp deletion,
two patients being homozygous. The presence of the CCR5 32-bp gene deletion
has also been analysed in 71 HIV-positive patients. In this group of
patients, there was a lower than expected incidence of the 32-bp deletion.
Those who possess the 32-bp deletion progress to AIDS more slowly than
those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower
in those heterozygous for the gene deletion.
We confirm that heterozygosity for the 32-bp gene deletion in CCR5
is partially protective against initial infection with HIV. In those
heterozygous patients who became infected with HIV, disease progression
was slower.
|
|
HIV-specific cytotoxic T lymphocytes, HLA-A11, and chemokine-related
factors may act synergistically to determine HIV resistance in CCR5
delta32-negative female sex workers in Chiang Rai, northern Thailand.
Sriwanthana B, Hodge T, Mastro TD, Dezzutti CS, Bond K, Stephens
HA, Kostrikis LG, Limpakarnjanarat K, Young NL, Qari SH, Lal RB, Chandanayingyong
D, McNicholl JM.
Department of Medical Sciences, Ministry of Public Health, Nonthaburi,
11000 Thailand.
|
AIDS Res Hum Retroviruses 2001 May 20;17(8):719-34 Abstract
quote
Understanding how highly HIV-exposed individuals remain HIV uninfected
may be useful for HIV vaccine design and development of new HIV prevention
strategies.
To elucidate mechanisms associated with resistance to HIV infection,
immunologic and genetic factors were examined in 14 HIV-exposed but
persistently seronegative (HEPS) female sex workers from Chiang Rai,
northern Thailand and in ethnically matched, HIV-positive (n = 9) and
HIV-negative women (n = 9). The HEPS women were identified in a study
of commercial sex workers who had an HIV-1 incidence of 20.3 per 100
person-years. A high frequency of HLA-A11 was observed in HEPS women
(86%) compared with northern Thai controls (56%). HIV-specific cytotoxic
T lymphocyte (CTL) lytic responses were detected in cryopreserved peripheral
blood mononuclear cells (PBMCs), using HLA-A-matched subtype E HIV-1
peptides in four of seven (57%) HEPS women, eight of eight HIV-positive
women, and zero of nine HIV-negative unexposed controls (p = 0.019 HEPS
women vs. HIV-negative controls). CTL lysis levels were low, but responses
were detected to peptides from Nef, Pol, Gag, and Env. Nef responses
predominated in HEPS women.
Compared with controls, HEPS women tended to have higher frequencies
of CCR5 promotor 59402GG and SDF-1 3'UTR 801A genotypes known to influence
HIV transmission or course of disease. HEPS women also had higher levels
of spontaneous RANTES production by PBMCs than other groups. Each of
these factors could potentially contribute to HIV resistance. As most
HEPS women had one or more of these factors, they may prevent HIV infection
synergistically by blocking HIV cell entry, delaying its dissemination,
or killing HIV-infected cells.
|
|
Polymorphism of CCR5 affecting HIV disease progression in the Japanese
population.
Kageyama S, Mimaya J, Yamada K, Kurimura T, Shiraki K; Research
Committee on Prevention of Developing Illness and Therapy for HIV-infected
People.
Department of Virology, Toyama Medical and Pharmaceutical University,
2630 Sugitani, Toyama 930-0194, Japan.
|
AIDS Res Hum Retroviruses 2001 Jul 20;17(11):991-5 Abstract
quote
Among several factors associated with HIV-1 disease progression, genetic
polymorphism of CCR2, CCR5, and CXCR4 in HIV-1 infection has been found.
Single-nucleotide polymorphisms (SNPs) in the CCR2, CCR5, and CXCR4
genes as well as a 32-base pair deletion in the open reading frame of
the CCR5 gene are associated with HIV disease progression among Caucasians
and African-Americans in North America and Europe. However, in populations
other than Caucasians and African-Americans, SNPs have not been fully
examined.
In our study SNPs in CCR2 coding and CCR5 regulatory regions have been
examined in 98 Japanese HIV-positive individuals. The alleles of CCR5
regulatory regions at -2135T and -2086G are associated with late onset
of AIDS (p < 0.05; odds ratio for the early onset of AIDS, 0.502
and 0.404, respectively). In contrast to this, the allele of CCR5 at
-2086A is associated with the early onset of AIDS (p < 0.05; odds
ratio for the early onset of AIDS, 2.133). A haplotype including two
alleles at -2135G and -2086G is associated with the late onset of AIDS
(p < 0.05; odds ratio for the early onset of AIDS, 0.372). Thus we
found that a CCR5 SNP and haplotype polymorphism affect HIV disease
progression even in the Japanese population.
This indicates that the CCR5 genetic polymorphism affecting disease
progression should be studied in a wider range of population.
|
|
Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease
progression: An international meta-analysis of individual-patient data.
Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL,
Buchbinder SP, Coutinho RA, Eugen-Olsen J, Gallart T, Katzenstein TL,
Kostrikis LG, Kuipers H, Louie LG, Mallal SA, Margolick JB, Martinez
OP, Meyer L, Michael NL, Operskalski E, Pantaleo G, Rizzardi GP, Schuitemaker
H, Sheppard HW, Stewart GJ, Theodorou ID, Ullum H, Vicenzi E, Vlahov
D, Wilkinson D, Workman C, Zagury JF, O'Brien TR; International Meta-Analysis
of HIV Host Genetics.
Department of Hygiene and Epidemiology, University of Ioannina School
of Medicine, Ioannina 45110, Greece.
|
Ann Intern Med 2001 Nov 6;135(9):782-95 Abstract quote
BACKGROUND: Studies relating certain chemokine and chemokine receptor
gene alleles with the outcome of HIV-1 infection have yielded inconsistent
results.
OBJECTIVE: To examine postulated associations of genetic alleles with
HIV-1 disease progression.
DESIGN: Meta-analysis of individual-patient data.
SETTING: 19 prospective cohort studies and case-control studies from
the United States, Europe, and Australia.
PATIENTS: Patients with HIV-1 infection who were of European or African
descent.
MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1
RNA level at study entry or soon after seroconversion. Data were combined
with fixed-effects and random-effects models.
RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated
with a decreased risk for progression to AIDS (relative hazard among
seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased
risk for death (relative hazard among seroconverters, 0.64 and 0.74;
P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion
(difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P
< 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had
no clear protective effect on the risk for death after development of
AIDS. The results were consistent between seroconverters and seroprevalent
patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk
for AIDS (relative hazard for seroconverters and seroprevalent patients,
0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00),
or death after development of AIDS (relative hazard, 0.81 and 0.97;
P > 0.5 for all).
CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective
effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity
carried no such protection.
|
|
Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain
of CC chemokine receptor 5 contribute to high affinity binding of chemokines.
Bannert N, Craig S, Farzan M, Sogah D, Santo NV, Choe H, Sodroski
J.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,
Boston, MA 02115, USA.
|
J Exp Med 2001 Dec 3;194(11):1661-73 Abstract quote
The chemokine receptor CCR5 plays an important role in leukocyte chemotaxis
and activation, and also acts as a coreceptor for human and simian immunodeficiency
viruses (HIV-1, HIV-2, and SIV).
We provide evidence that CCR5 is O-glycosylated on serine 6 in the
NH2 terminus. The O-linked glycans, particularly sialic acid moieties,
significantly contribute to binding of the chemokine ligands. By contrast,
removal of O-linked oligosaccharide exerted little effect on HIV-1 infection.
Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was
important for efficient beta-chemokine binding. Thus, as has been observed
for the binding of selectins and their ligands, O-linked carbohydrates
and tyrosine sulfates play major roles in promoting the interaction
of chemokines with CCR5. The resulting flexible arrays of negative charges
on the CCR5 surface may allow specific, high-affinity interactions with
diverse chemokine ligands.
Although this is the first example of O-linked oligosaccharides and
tyrosine sulfates playing a role in chemokine binding, the high density
of serines, threonines and tyrosines in the N-termini of many CC chemokine
receptors suggests that these posttranslational modifications may commonly
contribute to chemokine binding.
|
|
Chemokine-mediated block to HIV entry is associated with CCR5 internalization
efficiency.
Brandt SM, Mariani R, Holland AU, Hope TJ, Landau NR.
Infectious Disease Laboratory, Salk Institute for Biological Studies,
La Jolla, CA 92037.
|
J Biol Chem 2002 Jan 8 Abstract quote
Chemokines inhibit entry of HIV into CD4+ T cells more effectively
than into macrophages or transfected adherent cells. Here, we tested
whether chemokine receptor internalization could account for cell-type
differences in the effectiveness of chemokines. Infection of CEM T cells
expressing stably transduced wild-type CCR5 was much more readily inhibited
by chemokine than were transduced HOS cells.
This response correlated with the efficiency of CCR5 internalization.
A mutated CCR5, termed M7-CCR5, in which the potential Ser/Thr phosphorylation
sites in the cytoplasmic tail were changed to Ala did not internalize
in response to MIP-1a. M7-CCR5 was expressed at slightly higher levels
than wild-type on stably transduced cell lines and was somewhat more
potent as an HIV-1 coreceptor. The mutated receptor mobilized intracellular
Ca2+ in response to chemokine to a level four-fold higher than did the
wild type CCR5. Unexpectedly, the receptor was desensitized as efficiently
as wild-type, suggesting that desensitization does not require cytoplasmic
tail phosphorylation. Entry of R5 HIV-1 reporter virus into cells stably
expressing M7-CCR5 was largely resistant to blocking by MIP-1a. As much
as 80% of entry inhibition was attributed to receptor internalization.
AOP-MIP-1a was able to induce a low level of M7-CCR5 internalization
in HOS and to weakly inhibit HIV-1 entry. Introduction of dominant-negative
dynamin into HOS cells reduced the ability of chemokine to inhibit infection.
The inefficiency of internalization of chemokine receptors in some
cell-types could allow virus to replicate in vivo in the presence of
endogenous chemokine. Lastly, M7-CCR5 may be a useful tool for discriminating
coreceptor internalization from binding site masking mechanisms in the
evaluation of small molecule inhibitors of HIV-1 entry.
|
|
Analysis of CCR5Delta32 Geographic Distribution and Its Correlation
with Some Climatic and Geographic Factors.
Limborska SA, Balanovsky OP, Balanovskaya EV, Slominsky PA, Schadrina
MI, Livshits LA, Kravchenko SA, Pampuha VM, Khusnutdinova EK, Spitsyn
VA.
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow,
Russia.
|
Hum Hered 2002;53(1):49-54 Abstract quote
We studied the possible effects of climatic-geographic factors on the
world distribution of the mutant allele for the chemokine receptor gene
CCR5, which has a 32-bp deletion (CCR5Delta32) preventing cell invasion
by the primary transmitting strain of HIV-1. New data on CCR5 polymorphisms
in Russian, Ukrainian, and Moldavian populations are presented. All
available data on CCR5Delta32 frequencies in the Old World (number of
populations n = 77) were used for construction of a geographical gene
map to analyze possible correlations between allele frequencies and
eight climatic-geographic parameters.
A strong positive correlation was found between the allele frequency
and latitude (r = 0.72), a strong negative correlation with annual radiation
balance (r = -0.66), and a weaker negative correlation with longitude
(r = -0.34). Partial correlations were calculated excluding the influence
of latitude. The negative correlation between the allele frequency and
annual radiation balance decreased (r = -0.42), but remained large and
significant.
We propose that the existence of correlations between the cline of
CCR5Delta32 frequencies and climatic-geographic parameters provides
evidence for a possible effect of either natural environmental factors
or large-scale population movements on the distribution of this allele.
|
| CCR-CX3CR1 |
|
|
Rapid progression to AIDS in HIV+ individuals with a structural
variant of the chemokine receptor CX3CR1.
Faure S, Meyer L, Costagliola D, Vaneensberghe C, Genin E, Autran
B, Delfraissy JF, McDermott DH, Murphy PM, Debre P, Theodorou I, Combadiere
C.
Laboratoire d'Immunologie Cellulaire et Tissulaire, Centre National
de la Recherche Scientifique UMR 7627, Hopital Pitie-Salpetriere, Paris,
France.
|
Science 2000 Mar 24;287(5461):2274-7 Abstract
quote
Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and
a coreceptor.
Which of 15 known coreceptors are important in vivo is poorly defined
but may be inferred from disease-modifying mutations, as for CCR5. Here
two single nucleotide polymorphisms are described in Caucasians in CX3CR1,
an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the
chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249
M280, a variant haplotype affecting two amino acids (isoleucine-249
and methionine-280), progressed to AIDS more rapidly than those with
other haplotypes.
Functional CX3CR1 analysis showed that fractalkine binding is reduced
among patients homozygous for this particular haplotype. Thus, CX3CR1-I249
M280 is a recessive genetic risk factor in HIV/AIDS
|
| CYTOKINES |
|
|
The role of cytokines in the pathogenesis and management of AIDS-related
lymphomas.
Fassone L, Gaidano G, Ariatti C, Vivenza D, Capello D, Gloghini
A, Cilia AM, Buonaiuto D, Rossi D, Pastore C, Carbone A, Saglio G.
Department of Medical Sciences, Amedec Avogadro University of Eastern
Piedmont, Novara, Italy.
|
Leuk Lymphoma 2000 Aug;38(5-6):481-8 Abstract quote
AIDS-related non-Hodgkin lymphomas (AIDS-NHL) consistently derive from
B-cells and are characterized by extreme clinical aggressiveness. At
histological level, AIDS-NHL are classified as AIDS-related Burkitt's
lymphoma (AIDS-BL), AIDS-related diffuse large cell lymphoma (AIDS-DLCL)
and AIDS-related primary effusion lymphoma (AIDS-PEL). The role of cytokines
in the pathogenesis and management of AIDS-NHL has been studied to a
certain extent.
Production of large quantities of human IL-10 occurs frequently in
AIDS-BL and correlates with latent EBV infection of the tumor clone.
Lesser amounts of the cytokine are released in EBV negative cases. The
pathogenetic role of IL-10 in AIDS-BL is suggested by the observation
that IL-10 antisense oligonucleotides inhibit proliferation of the lymphoma.
A significant fraction of AIDS-BL cell lines produce TNFbeta. Among
AIDS-NHL, the release of TNFbeta appears to be specific for AIDS-BL.
The pathogenetic relevance of TNFbeta in lymphomagenesis is suggested
by the observation that some BL cell lines use TNFbeta as an autocrine
growth factor. Some cases of AIDS-BL, particularly those carrying EBV
infection, also secrete IL-6, IL-7 and IL-12. With respect to AIDS-DLCL,
many cases express the IL-6R, rendering these cells responsive to the
paracrine stimulation by the IL-6 produced by nearby T-cells, macrophages
and endothelial cells which are frequently abundant in these tumor samples.
The tumor clone itself, however, generally fails to release IL-6. AIDS-PEL
is characterized by secretion of large amounts of IL-6 and IL-10. Some
PEL cases also release oncostatin M. Apart from human IL-6, PEL also
express viral IL-6, which is encoded by the HHV-8 genome. The biological
relevance of both IL-6 and IL-10 in PEL proliferation and growth has
been recently clarified in vitro and in vivo.
Overall, these data suggest that activation of different cytokine loops
clusters with different clinico-pathologic categories of AIDS-NHL and
may represent the potential target of novel therapeutic strategies.
|
| FAS ONCOGENE |
|
|
Regulation of Fas Expression in the Lymph Nodes of Patients Infected
With Human Immunodeficiency Virus
Liqiang Wang, MD, PhD and Patrick A. Adegboyega, MD
From the Department of Pathology, The University of Texas Medical
Branch, Galveston, Tex.
|
Arch Pathol Lab Med 2002;126, No. 1, pp. 28–32. Abstract quote
Context.—The mechanism by which human immunodeficiency virus 1 (HIV-1)
infection causes increased rates of apoptosis and gradual chronic depletion
of CD4+ T lymphocytes in patients infected with HIV-1 is not known.
Findings from in vitro culture studies and analysis of mononuclear cells
in the peripheral blood of HIV-infected patients have led to the hypothesis
that abnormal expression and/or interaction of Fas and Fas ligand (FasL)
may play significant roles in the derangement of homeostasis of CD4+
lymphocytes in patients infected with HIV-1.
Objective.—To determine the in situ expression of Fas and FasL in the
lymph nodes of patients infected with HIV-1. Design.—Immunohistochemical
expression of Fas and FasL was studied in the lymph node biopsy specimens
from 20 patients infected with HIV-1. As controls, we also studied 120
lymph nodes from 28 HIV-1–seronegative patients with reactive lymphadenopathy.
Results.—In the reactive lymph nodes of seronegative patients, expression
of Fas was diffuse in the germinal centers and also in immunoblast-like
cells in the T-cell regions. In the lymph nodes of patients infected
with HIV, there was a consistent remarkable decrease in Fas expression
in 12 of 20 patients and a total lack of Fas expression in the remaining
8 patients. Expression of FasL was comparable in both patient groups.
Conclusions.—There is marked down-regulation of Fas in the lymph nodes
of HIV-infected patients, a sharp contrast to what occurs in circulating
mononuclear cells in the peripheral blood of these patients. These results
indicate the need for further studies of this molecular event for possible
therapeutic intervention based on reconstitution of Fas and/or FasL
activity in the treatment of HIV infection.
|
| IMMUNOSUPPRESSION |
|
| HIV-1 and causal relationship to immunosuppression and
nervous system disease in AIDS |
Hum Pathol 2000;31:1274-1298
|
| LECTINS |
|
|
Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR:
Consequences for HIV infection and immunity.
Soilleux EJ, Morris LS, Rushbrook S, Lee B, Coleman N.
Medical Research Council Cancer Centre Unit, Hutchison/MRC Research
Centre, Cambridge, UK; Department of Medicine, Addenbrooke's Hospital,
Hills Road, Cambridge, UK; and Department of Microbiology, Immunology
& Molecular Genetics, UCLA, Los Angeles, CA.
|
Hum Pathol 2002 Jun;33(6):652-9 Abstract quote
DC-SIGNR is a human immunodeficiency virus (HIV)-binding C-type lectin
that is expressed on endothelium in the hepatic sinusoids, lymph node
sinuses and placenta. Like closely related DC-SIGN, DC-SIGNR can bind
both ICAM-3 and HIV and can potentiate HIV infection of T lymphocytes
in trans.
In the present study we have investigated reasons underlying the restricted
distribution of DC-SIGNR and have examined DC-SIGNR expression in relation
to HIV entry receptors. We show that DC-SIGNR expression does not depend
on endothelial cell specialization or on activation state. DC-SIGNR-positive
endothelium continues to express DC-SIGNR in conditions of hyperplasia,
whereas the molecule is lost after neoplastic transformation, most likely
as a result of changes in the microenvironment of the endothelial cells.
We have further shown that CCR5, but not CD4, is coexpressed with DC-SIGNR
on hepatic sinusoidal and placental capillary endothelial cells. However,
CD4-positive CCR5-positive cells, such as hepatic Kupffer cells, placental
Hofbauer cells, and CD4-positive T lymphocytes in lymph nodes, can be
found adjacent to DC-SIGNR-positive endothelium. Therefore, DC-SIGNR
may be able to mediate HIV infection of these cells in trans. Finally,
we demonstrate that DC-SIGN and DC-SIGNR can be coexpressed on lymph
node sinus endothelial cells, which may lead to modulation of the function
of both molecules.
|
| RB2/p130 TUMOR SUPPRESSOR GENE |
|
|
Expression of RB2/p130 tumor-suppressor gene in AIDS-related non-Hodgkin's
lymphomas: implications for disease pathogenesis.
Lazzi S, Bellan C, De Falco G, Cinti C, Ferrari F, Nyongo A, Claudio
PP, Tosi GM, Vatti R, Gloghini A, Carbone A, Giordano A, Leoncini L,
Tosi P.
Institute of Pathological Anatomy and Histology, University of Siena,
Siena, Italy.
|
Hum Pathol 2002 Jul;33(7):723-31 Abstract quote
In this study we examined 21 cases of AIDS-related lymphomas for genomic
organization and expression of RB2/p130 oncosuppressor gene and compared
the results with the proliferative features of these neoplasms.
We found no mutations in the RB2/p130 gene and unusually high percentages
of cells expressing nuclear pRb2/p130 in tumors with a high proliferative
activity, such as AIDS-related lymphomas. These findings might suggest
that a molecular mechanism usually observed in viral-linked oncogenesis
could be involved. We performed in vitro and in vivo binding assays
to investigate whether the human immunodeficiency virus (HIV) gene product
Tat and Rb2/p130 could interact. The results of these assays revealed
that the HIV-1 Tat protein binds specifically to pRb2/p130. This may
result in the inactivation of its oncosuppressive properties and the
induction of genes needed to proceed through the cell cycle including
p107, cyclin A, and cyclin B.
Using single-cell polymerase chain reaction (PCR) assay, we found HIV-1
DNA in the neoplastic cells of only 2 of the 21 cases examined, whereas
PCR on whole tissue revealed HIV-1 DNA in all of the cases. Furthermore,
a diffuse and nuclear stain was observed in tissue sections with anti-Tat
monoclonal antibody. These findings are in accordance with the notion
that soluble Tat protein could function as a biologically active extracellular
protein released by infected cells and taken up readily by uninfected
B cells. In conclusion, our results seem to suggest that pRb2/p130 oncosuppressor
protein may be a target in the interaction between the HIV-1 gene products
and host proteins.
|
| LABORATORY/
RADIOLOGIC/
OTHER TESTS |
CHARACTERIZATION |
| Laboratory Markers |
|
| Screening |
|
| EIA test |
Must be repeatedly reactive
If patient has repeatedly reactive tests but negative confirmatory
test, considered uninfected unless viral culture, PCR, and p24 antigen
testing is positive
May not detect antibodies until one to two months after infection |
| Confirmation Test |
|
| Western Blot or IFA test |
|
| Disease progression |
|
| Viral load |
Measures viral RNA in plasma but does not measure viral
load in the lymph or other tissues |
| Branched DNA (bDNA) |
Directly quantify viral RNA at physiologic levels and highly
accurate |
| ANA/ANCA/BASEMENT MEMBRANE ANTIBODIES |
|
| Anti-nuclear, anti-neutrophil cytoplasmic and anti-glomerular
basement membrane antibodies in HIV-infected individuals.
Savige JA, Chang L, Horn S, Crowe SM.
University Department of Medicine, Austin Hospital, Heidelberg,
Victoria, Australia. |
Autoimmunity 1994;18(3):205-11 Abstract quote
Many autoantibodies have been described in HIV-infected individuals.
We have examined the incidence, associations and prognostic significance
of anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies
(ANCA) and anti-glomerular basement membrane (GBM) antibodies in individuals
with HIV infections.
One hundred and five patients, with asymptomatic infections (n = 37),
AIDS-related complex (n = 32) or AIDS (n = 36) were studied.
Plasma from 24 of these (23%) were positive for ANA: most demonstrated
speckled fluorescence (n = 21) and were of low titre (1+ in 18). ANCA
were demonstrated by IIF in 18 individuals (17%) and all fluorescent
patterns were seen; 6 of these plasma were also positive in the ELISAs
for antibodies to proteinase 3, myeloperoxidase or elastase. Thirteen
plasma were positive for ANCA in the neutrophil cytoplasm ELISA; 10
of these were also positive in the specific ELISAs. A total of 30 plasma
bound to proteinase 3, myeloperoxidase or elastase in specific ELISAs,
in 6 cases with 2 specificities. Finally, 18 plasma (17%) contained
anti-GBM antibodies by ELISA, but none of 4 plasma tested in inhibition
assays was specific.
ANA, ANCA and anti-GBM antibodies were not uncommon in HIV-infected
individuals but the presence of these antibodies was not associated
with the clinical manifestations of the corresponding autoimmune diseases.
In addition, there was no correlation between the demonstration of these
antibodies and the immunological status of the individual (apart from
a correlation between CD4 counts less than 400/microliters with anti-GBM
antibodies), the presence of an opportunistic infection, the development
of malignancy or reduced survival. Some of these antibodies may arise
from polyclonal activation, or be due to "sticky" serum since we have
shown that the presence of anti-GBM antibodies correlated with the demonstration
of ANCA by ELISA. These antibodies are not more common in hypergammaglobulinemic
plasma but some may be due to heat-treatment of the plasma.
The clinician caring for HIV-infected individuals needs to be aware
of these "false-positive" antibody results. |
| LIPID LEVELS |
|
Impact of HIV Infection and HAART on Serum Lipids in Men.
Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella
F, Visscher B, Evans R, Kingsley LA.
University of Pittsburgh, Pittsburgh, Pa.
|
JAMA. 2003 Jun 11;289(22):2978-82. Abstract quote
CONTEXT: Alterations in serum lipid values have been widely reported
among persons infected with human immunodeficiency virus (HIV) type
1 treated with highly active antiretroviral therapy (HAART), but no
data have yet been reported on changes from preseroconversion lipid
values.
OBJECTIVE: To describe changes in serum cholesterol levels associated
with HIV infection and antiretroviral medication exposure, and 1-time
assessment of triglyceride levels post-HAART initiation.
DESIGN, SETTING, AND PARTICIPANTS: The Multicenter AIDS Cohort Study,
a prospective study in which homosexual and bisexual men were enrolled
and from which 50 of 517 HIV seroconverters were drawn for the analysis
herein, who later initiated HAART, involving measurements of stored
serum samples obtained between 1984 and 2002.
MAIN OUTCOME MEASURES: Changes in levels of total cholesterol (TC),
high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein
cholesterol (LDL-C) at 6 time points during an average of 12 years;
1-time assessment of triglyceride levels from the third post-HAART clinic
visit. RESULTS: Among the 50 men, notable declines in mean serum TC
(-30 mg/dL [-0.78 mmol/L]), HDL-C (-12 mg/dL [-0.31 mmol/L]), and LDL-C
values (-22 mg/dL [-0.57 mmol/L]) were observed after HIV infection.
Following HAART initiation, there were large increases in mean TC and
LDL-C values (50 and 21 mg/dL [1.30 and 0.54 mmol/L], respectively);
however, the mean changes from the preseroconversion values were 20
mg/dL (0.52 mmol/L) (95% confidence interval [CI], -1 to 41) and -1
mg/dL (-0.03 mmol/L) (95% CI, -25 to 22), respectively. Mean HDL-C remained
below baseline levels throughout follow-up. The median value (interquartile
range) of triglycerides was 225 mg/dL (2.54 mmol/L) (147-331 mg/dL).
CONCLUSIONS: Before treatment, HIV infection results in substantial
decreases in serum TC, HDL-C, and LDL-C levels. Subsequent HAART initiation
is associated with increases in TC and LDL-C but little change in HDL-C.
Increases in TC and LDL-C observed after about 3 years of HAART possibly
represent a return to preinfection serum lipid levels after accounting
for expected age-related changes.
|
| VIRAL LOAD RNA |
|
Lowering the Detection Limits of HIV-1 Viral Load Using Real-Time Immuno-PCR for HIV-1 p24 Antigen
Janet M. Barletta, PhD, Daniel C. Edelman, MS, and Niel T. Constantine, PhD
|
Am J Clin Pathol 2004;122:20-27 Abstract quote
Presently, the assay that attains maximal sensitivity and dynamic range of HIV-1 viral copy number (50 copies per milliliter) is nucleic acid amplification of HIV RNA in plasma. Enzyme-linked immunosorbent assay (ELISA) methods for quantification of HIV-1 p24 antigen have been relatively insensitive.
In this report, we show data that indicate real-time immuno–polymerase chain reaction (IPCR), a combination of the ELISA and PCR techniques, is more sensitive for HIV-1 p24 antigen detection than other currently reported methods. When derived from an IPCR standard curve, a dose response was observed from patient samples with known viral loads diluted within a 3-log range (1.68-6,514 viral RNA copies per milliliter). IPCR detected 42% (22/52) of patient samples that had fewer than 50 viral RNA copies per milliliter by reverse transcriptase–PCR.
IPCR shows the potential to become the most analytically sensitive test available for determination of HIV-1 viral load by the detection of HIV-1 p24 antigen. |
| A Modified Ultrasensitive Assay to Detect Quantified HIV-1 RNA
of Fewer Than 50 Copies per Milliliter
Estelle M. Piwowar-Manning, MT, SI,1 Terry A. Henderson, MT,1 Lorraine
Brisbin, MS,2 and J. Brooks Jackson, MD, MBA
|
Am J Clin Pathol 2003;120:268-270 Abstract quote
We compared the sensitivity and specificity of versions 1.0 and 1.5
and a modified version 1.5 of the AMPLICOR HIV-1 MONITOR ultrasensitive
RNA assay (Roche, Indianapolis, IN) by using a virus stock dilution
series and plasma samples from HIV-1– infected and uninfected
subjects.
The modified assay was linear and consistently positive down to 12 copies
per milliliter vs 25 copies per milliliter for the other 2 assays. Versions
1.0, 1.5, and modified 1.5, respectively, detected 9 (23%) of 39, 11
(28%) of 40, and 43 (61%) of 71 replicates of a 4-copy-number and 11
(28%) of 40, 17 (46%) of 37, and 88 (90%) of 98 replicates of a 10-copy-number
standard. Of 44 patient samples with undetectable levels using version
1.0, 32 (73%) had detectable levels on the modified assay, and 5 (25%)
of 20 had detectable levels on version 1.5.
None of the assays detected HIV-1 RNA in HIV-1 antibody–negative
samples. The modified version 1.5 of the RNA assay is more sensitive
for detecting HIV-1 RNA in significantly more patients than are versions
1.0 and 1.5. |
|
Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter
Hemophilia Cohort Study.
O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen
AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ, Kroner
BL, Goedert JJ.
Viral Epidemiology Branch, National Cancer Institute, Rockville,
MD 20852, USA.
|
JAMA 1996 Jul 10;276(2):105-10 Abstract quote
OBJECTIVE--To determine if the long-term incidence of the acquired
immunodeficiency syndrome (AIDS) is related to human immunodeficiency
virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection.
DESIGN--Epidemiologic cohort study.
SETTING--Five hemophilia treatment centers in the United States.
SUBJECTS--A total of 165 subjects with hemophilia and HIV-1 infection
(age at HIV-1 seroconversion, 1-66 years) followed from 1979 to 1995.
METHODS--The HIV-1 RNA level was measured by polymerase chain reaction
over a range of 200 to 1 million or more HIV-1 RNA copies/mL in archived
serum specimens collected 12 to 36 months (median, 27 months) after
the estimated date of HIV-1 seroconversion. Kaplan-Meier methods were
used to examine the risk of AIDS and proportional hazards models were
used to estimate relative hazards.
RESULTS--The HIV-1 RNA values were similar in subjects younger than
17 years at seroconversion (median, 5214 copies/mL) and those 18 to
34 years old (median, 4693 copies/mL), but higher in those 35 years
or older (median, 12069 copies/mL) (P = .02 compared with each younger
group). At 10 years after seroconversion, the proportions of subjects
with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL
measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among
subjects with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects
with 1000 to 9,999 copies/mL (n = 82), and 0% among subjects with fewer
than 1000 copies/mL (n = 19) (P < .001). The age-adjusted relative
hazard for AIDS for subjects with 10,000 or more copies/mL was 14.3
(95% confidence interval, 1.9-105.6) compared with subjects with fewer
than 1000 copies/mL.
CONCLUSIONS--The HIV-1 RNA level during early chronic HIV-1 infection
is a strong, age-independent predictor of clinical outcome; low levels
define persons with a high probability of long-term AIDS-free survival. |
|
Effects of plasma HIV RNA, CD4+ T lymphocytes, and the chemokine receptors
CCR5 and CCR2b on HIV disease progression in hemophiliacs. Hemophilia
Growth and Development Study.
Daar ES, Lynn H, Donfield S, Gomperts E, Hilgartner MW, Hoots K,
Chernoff D, Winkler C, O'Brien SJ.
Cedars-Sinai Burns & Allen Research Institute, Department of
Medicine, and the University of California Los Angeles School of Medicine,
90048, USA. |
J Acquir Immune Defic Syndr 1999 Aug 1;21(4):317-25 Abstract
quote
We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes
and chemokine receptors CCR5 and CCR2b on HIV disease progression in
hemophiliacs.
We prospectively observed during follow-up 207 HIV-infected hemophiliacs
in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured
on cryopreserved plasma from enrollment using the Chiron Corporation
bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32
were detected using standard molecular techniques. Those with the mutant
allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV
RNA, and higher CD4+ T lymphocytes than did those without these genetic
variants. After controlling for the effects of plasma HIV RNA and CD4+
T lymphocytes, those with the CCR2b mutant allele compared with those
wild-type, had a trend toward a lower risk of progression to AIDS, adjusted
relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p =
.092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00;
p = .059).
We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes
are correlated, and the protective affect of CCR2b against HIV disease
progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte
number |
| PROGNOSIS AND TREATMENT |
CHARACTERIZATION |
| PROGNOSIS |
|
| GENERAL |
|
| Autopsy Findings in a Human Immunodeficiency
Virus–Infected Population Over 2 Decades
Influences of Gender, Ethnicity, Risk Factors, and Time
Susan Morgello, MD, Rashid Mahboob, MD, Tatiana Yakoushina, MD, Shafat
Khan, MD, and Karin Hague, MD
From the Manhattan HIV Brain Bank, Department of Pathology,
Division of Neuropathology, the Mount Sinai Medical Center, New York,
NY
|
Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 182–190.
Abstract quote
Objectives.—To examine autopsy pathology in an urban population
infected with the human immunodeficiency virus (HIV) and to determine
if age at death and disease frequencies are associated with gender,
HIV risk factors, ethnicity, and therapeutic era.
Design and Methods.—Retrospective analysis of autopsy data from
394 HIV-infected adults. The population was divided into 3 therapeutic
eras for analysis: group A, 1979–1986; group B, 1987–1995;
and group C, 1996–2000.
Results.—Women died at significantly younger ages than men (mean
± SEM age, 38.9 ± 1.0 years vs 42.5 ± 0.64 years),
even after adjustment for risk factors, ethnicity, and therapeutic era.
This age discrepancy occurred despite a lower prevalence of arteriosclerosis,
cachexia, and hepatitis B in women and no significant differences in
the frequencies of other infectious diseases. Whites had a longer survival
than patients of other ethnicities (mean age at death, 44.7 ±
1.2 years for whites, 39.9 ± 0.80 years for blacks, and 41.3
± 0.87 years for Hispanic individuals). Renal, cardiac, and splenic
pathologies, Mycobacterium avium-intracellulare (MAI) infection, and
cachexia were more common in blacks than in whites and/or Hispanic individuals,
and cytomegalovirus and systemic lymphoma were more common in whites
and Hispanic individuals than in blacks. Diseases associated with intravenous
drug use were hepatitis C, cirrhosis, and tuberculosis; those with all
sexual risk factors, cytomegalovirus infection, herpes simplex virus
infection, and Pneumocystis carinii pneumonia; and those with homosexual
risk, Kaposi sarcoma and MAI infection. The prevalence of many disease
entities changed over time: compared with the other groups, group C
had lower prevalences of many viral and fungal illnesses, MAI infection,
systemic lymphoma, cachexia, and Kaposi sarcoma and higher prevalences
of hepatitis, cirrhosis, arteriosclerosis, staphylococcal and streptococcal
infections, and traumatic lesions. When the data were adjusted for changing
demographic and risk composition, the only significant changes in disease
frequency for period C were decreased prevalences of PCP and Kaposi
sarcoma and increased prevalences of cirrhosis and arteriosclerosis.
Conclusions.—Significant gender- and ethnicity-related differences
in age of death occurred in this HIV-infected population, and these
differences were not explained by the frequencies of diseases. The lower
prevalences of PCP and Kaposi sarcoma in group C are likely a reflection
of the impact of potent therapies on causes of mortality. The higher
prevalences of cirrhosis and arteriosclerosis suggest that entities
not targeted by antiretroviral reconstitution of immunity will play
an increasingly important role in HIV-related mortality in the future. |
| MALIGNANCIES |
|
Risk factors for pediatric human immunodeficiency virus-related malignancy.
Pollock BH, Jenson HB, Leach CT, McClain KL, Hutchison RE,
Garzarella L, Joshi VV, Parmley RT, Murphy SB.
Children's Cancer Research Institute.
|
JAMA 2003 May 14;289(18):2393-9 Abstract quote CONTEXT: Although
cancers occur with increased frequency in children with human immunodeficiency
virus (HIV) infection, the specific clinical, immunological, and viral
risk factors for malignancy have not been identified.
OBJECTIVE: To identify risk factors for malignancy among HIV-infected
children.Design, Setting, and
PATIENTS: A multicenter case-control study of children with HIV at 26
institutions participating in the Pediatric Oncology Group. Forty-three
case patients with a new malignancy and 74 control patients without
a malignancy were matched based on the duration of their infection.
Patients were enrolled between January 1992 and July 1998.
MAIN OUTCOME MEASURES: Clinical and laboratory factors assessed as putative
risk factors included demographic characteristics, HIV characteristics,
prior antiretroviral treatment, and CD4 cell count. Coviral infections
with Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus
6 were assessed by semiquantitative polymerase chain reaction assays
and serological testing.
RESULTS: Case malignancy diagnoses included 28 non-Hodgkin lymphoma,
4 B-cell acute lymphoblastic leukemia, 1 Hodgkin disease, 8 leiomyosarcoma,
1 hepatoblastoma, and 1 schwannoma. Epstein-Barr virus viral load of
more than 50 viral genome copies per 105 peripheral blood mononuclear
cells was strongly associated with cancer risk but only for children
with CD4 cell counts of at least 200/ micro L (odds ratio [OR], 11.33;
95% confidence interval [CI], 2.09-65.66, P<.001). High EBV viral
load was not associated with cancer for children with CD4 cell counts
of less than 200/ micro L (OR, 1.12; 95% CI, 0.13-9.62; P =.99). Zidovudine
antiretroviral therapy did not confer a significant protective effect
for either the high (OR, 0.81; 95% CI, 0.22-3.09; P =.77) or the low
CD4 cell count groups (OR, 0.27; 95% CI, 0.04-1.46; P =.16). The route
of HIV infection was not associated with increased cancer risk.
CONCLUSIONS: Route of infection, demographic characteristics, and zidovudine
use were not associated with the development of malignancy in HIV-infected
children. High viral burden with EBV was associated with the development
of malignancy in HIV-infected children although the effect was modified
by CD4 cell count. The pathogenesis of HIV-related pediatric malignancies
remains unclear and other contributing risk factors can be elucidated
only through further study.
|
| PLASMA HIV-1 RNA |
|
| Initial Plasma HIV-1 RNA Levels and
Progression to AIDS in Women and Men
Timothy R. Sterling, M.D., David Vlahov, Ph.D., Jacquie
Astemborski, M.H.S., Donald R. Hoover, Ph.D., M.P.H., Joseph B. Margolick,
M.D., Ph.D., and Thomas C. Quinn, M.Dng |
N Engl J Med 2001;344:720-725 Abstract quote
Background
It is unclear whether there are differences between men and women with
human immunodeficiency virus type 1 (HIV-1) infection in the plasma
level of viral RNA (the viral load). In men, the initial viral load
after seroconversion predicts the likelihood of progression to the acquired
immunodeficiency syndrome (AIDS), but the relation between the two has
not been assessed in women. Currently, the guidelines for initiating
antiretroviral therapy are applied uniformly to women and men.
Methods
From 1988 through 1998, the viral load and the CD4+ lymphocyte count
were measured approximately every six months in 156 male and 46 female
injection-drug users who were followed prospectively after HIV-1 seroconversion.
Results
The median initial viral load was 50,766 copies of HIV-1 RNA per milliliter
in the men but only 15,103 copies per milliliter in the women (P<0.001).
The median initial CD4+ count did not differ significantly according
to sex (659 and 672 cells per cubic millimeter, respectively). HIV-1
infection progressed to AIDS in 29 men and 15 women, and the risk of
progression did not differ significantly according to sex. For each
increase of 1 log in the viral load (on a base 10 scale), the hazard
ratio for progression to AIDS was 1.55 (95 percent confidence interval,
0.97 to 2.47) among the men and 1.43 (95 percent confidence interval,
0.76 to 2.69) among the women. The median initial viral load was 77,822
HIV-1 RNA copies per milliliter in the men in whom AIDS developed and
40,634 copies per milliliter in the men in whom it did not; the corresponding
values in the women were 17,149 and 12,043 copies per milliliter. Given
the recommendation that treatment should be initiated when the viral
load reaches 20,000 copies per milliliter, 74 percent of the men but
only 37 percent of the women in our study would have been eligible for
therapy at the first visit after seroconversion (P<0.001).
Conclusions
Although the initial level of HIV-1 RNA was lower in women than in men,
the rates of progression to AIDS were similar. Treatment guidelines
that are based on the viral load, rather than the CD4+ lymphocyte count,
will lead to differences in eligibility for antiretroviral treatment
according to sex. |
| PREVENTION |
|
| Interventions to prevent HIV risk behaviors.
National Institutes of Health Consensus Development Conference Statement
February 11-13, 1997. |
AIDS 2000 Sep;14 Suppl 2:S85-96 Abstract quote
OBJECTIVE: To provide health care providers, patients, and the general
public with a responsible assessment of behavioral intervention methods
that may reduce the risk of HIV infection.
PARTICIPANTS: A non-Federal, nonadvocate, 12-member panel representing
the fields of psychiatry, psychology, behavioral and social science,
social work, and epidemiology. In addition, 15 experts in psychiatry,
psychology, behavioral and social science, social work, and epidemiology
presented data to the panel and a conference audience of 1000.
EVIDENCE: The literature was searched through Medline and an extensive
bibliography of references was provided to the panel and the conference
audience. Experts prepared abstracts with relevant citations from the
literature. Scientific evidence was given precedence over clinical anecdotal
experience.
CONSENSUS PROCESS: The panel, answering predefined questions, developed
its conclusions based on the scientific evidence presented in open forum
and the scientific literature. The panel composed a draft statement
that was read in its entirety and circulated to the experts and the
audience for comment. Thereafter, the panel resolved conflicting recommendations
and released a revised statement at the end of the conference. The panel
finalized the revisions within a few weeks after the conference.
CONCLUSIONS: Behavioral interventions to reduce risk for HIV/AIDS are
effective and should be disseminated widely. Legislative restriction
on needle exchange programs must be lifted because such legislation
constitutes a major barrier to realizing the potential of a powerful
approach and exposes millions of people to unnecessary risk. Legislative
barriers that discourage effective programs aimed at youth must be eliminated.
Although sexual abstinence is a desirable objective, programs must include
instruction on safer sex behaviors. The erosion of funding for drug
abuse treatment programs must be halted because research data clearly
show that such programs reduce risky drug abuse behavior and often eliminate
drug abuse itself. Finally, new research must focus on emerging risk
groups such as young people, particularly those who are gay and who
are members of ethnic minority groups, and women, in whom transmission
of HIV virus to their children remains a major public health problem. |
| TREATMENT |
|
| HAART |
|
| Randomized, controlled phase II trial of subcutaneous
interleukin-2 in combination with highly active antiretroviral therapy
(HAART) in HIV patients.
Hengge UR, Goos M, Esser S, Exner V, Dotterer H, Wiehler H, Borchard
C, Muller K, Beckmann A, Eppner MT, Berger A, Fiedler M.
Department of Dermatology and Venerology, University of Essen, Germany.
|
AIDS 1998 Dec 3;12(17):F225-34 Abstract quote
OBJECTIVE: To determine the immunological, virological and clinical
effects of subcutaneous IL-2 in 44 HIV-patients in conjunction with
pre-existing tri-therapy (zidovudine, 3TC, saquinavir). DESIGN: Partially
randomized, controlled, prospective trial.
SETTING: Single center study at tertiary care center.
PATIENTS: Sixty four patients (CD4 count 200-500 x 10(6)/l).
INTERVENTION: Fourty four patients were randomized to receive 5-day
cycles of IL-2 (9 Mio IU/d) every 6 weeks (Group A) or whenever the
CD4 cell count dropped below the 1.25-fold of baseline (Group B), whereas
20 control patients received the same HAART without IL-2. Outcome measures:
The optimal individual treatment interval and the immunological and
virological effects of subcutaneously administered IL-2 were analysed.
Importantly, the level of cellular in vivo immunity and the frequency
of dermatological marker diseases and infectious complications were
assessed.
RESULTS: IL-2 was well tolerated although fever, influenza-like symptoms
and indurated injection sites were commonly encountered. After 1 year
of IL-2, there was a median increase of more than 100 x 10(6)/l CD4
cells in both IL-2 groups in contrast to the controls (P < 0.01, 0.01
and not significant). The median HIV load did not increase either in
plasma or in lymph nodes. Lymphocyte activation decreased as assessed
by MHC class II (P < 0.001), CD25 (P < 0.001) and CD38 expression (P
¥ 0.005). Although delayed type hypersensitivity against common recall
antigens increased in both IL-2 groups, it did not reach statistical
significance. However, it is of note, that in 7 of 11 (63.6%) patients
delayed type hypersensitivity against recombinant HIV antigens improved
significantly. Whereas there was no opportunistic infection in either
IL-2 group, three cases of Kaposi's sarcoma occurred in the controls.
Dermatological indicator diseases (thrush, condyloma, herpes simplex)
were found to occur more frequently in the control group.
CONCLUSIONS: Subcutaneous IL-2 in addition to HAART was safe and led
to sustained qualitative and quantitative immunological improvements
in the majority of patients. Individualisation of therapy intervals
further improved the efficacy and tolerance of IL-2. |
| High dose therapy and autologous stem cell transplantation
for human immunodeficiency virus-associated non-Hodgkin lymphoma in
the era of highly active antiretroviral therapy.
Molina A, Krishnan AY, Nademanee A, Zabner R, Sniecinski I, Zaia
J, Forman SJ.
Division of Hematology and Bone Marrow Transplantation, City of
Hope National Medical Center, Duarte, California 91010, USA. |
Cancer 2000 Aug 1;89(3):680-9 Abstract quote
BACKGROUND: The advent of highly active antiretroviral therapy (HAART)
has allowed the exploration of more dose-intensive therapy such as autologous
stem cell transplantation (ASCT) in selected patients with human immunodeficiency
virus (HIV)-associated non-Hodgkin lymphoma (NHL).
METHODS: The authors report on the use of myeloablative chemotherapy
with ASCT in two HIV positive patients with NHL. The first patient underwent
ASCT at the time of first disease remission for poor risk, diffuse,
large cell NHL and the second patient had multiply recurrent, chemosensitive
Burkitt lymphoma. ASCT was performed in both patients using a transplant
conditioning regimen of high dose cyclophosphamide, carmustine, and
etoposide (CBV).
RESULTS: The target dose of >/= 5 x 10(6)/kg CD34 positive peripheral
blood stem cells (PBSC) utilized for ASCT was collected using granulocyte-colony
stimulating factor (G-CSF) after chemotherapy for mobilization while
both patients were receiving concomitant HAART for HIV infection. HAART
was continued during CBV conditioning. Prompt hematopoietic recovery
was observed after ASCT. Both patients remained in clinical disease
remission from their lymphoma at 28 months and 20 months after transplant,
respectively.
CONCLUSIONS: ASCT is feasible in patients with HIV-associated NHL.
Adequate numbers of CD34 positive PBSC can be procured from patients
receiving HAART and chemotherapy for NHL. Selected patients with HIV-related
lymphoma can tolerate the high dose CBV myeloablative chemotherapy regimen
without increased acute regimen-related toxicity. Reinfusion of G-CSF-mobilized
PBSC can lead to rapid recovery of hematologic function and sustained
engraftment after ASCT. Given the poor prognosis of patients with HIV-associated
NHL treated with conventional chemotherapy, further investigation of
this approach should be considered. |
| Prospective randomized two-Arm controlled study to
determine the efficacy of a specific intervention to improve long-term
adherence to highly active antiretroviral therapy.
Tuldra A, Fumaz CR, Ferrer MJ, Bayes R, Arno A, Balague M, Bonjoch
A, Jou A, Negredo E, Paredes R, Ruiz L, Romeu J, Sirera G, Tural C,
Burger D, Clotet B.
HIV Unit, "Fundacio Lluita SIDA" and "IrsiCaixa" Retrovirology
Laboratory, "Germans Trias i Pujol" University Hospital, Badalona, Spain. |
J Acquir Immune Defic Syndr 2000 Nov 1;25(3):221-8 Abstract
quote
BACKGROUND: Nearly perfect compliance seems to be indispensable to
obtain the maximum benefit from highly active antiretroviral therapy
(HAART). Interventions to ensure a high level of adherence during a
relatively long-term period of therapy are necessary.
METHODS: This is a prospective, randomized, two-arm controlled study
including patients starting their first-or second-line HAART who were
randomized to receive psychoeducative intervention to implement adherence
(experimental group [EG]) or a usual medical follow-up (control group
[CG]). We aimed to study the efficacy of a psychoeducative intervention
to ensure long-term adherence to HAART, its relation with the virologic
efficacy of treatment, and to determine the variables related to long-term
adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection.
Self-reported adherence was registered at each visit and its veracity
was tested by randomized blood analyses performed without previous warning
to 40% of patients. Appropriate adherence was defined as the consumption
of >/=95% of medication prescribed. Statistical analyses were performed
both by the as treated (AT) and the intention to treat missing = failure
(ITT) methods.
RESULTS: In all, 116 patients were included. At week 48, 94% of patients
in the EG versus 69% controls achieved adherence >/=95% (p =.008); 89%
of patients in the EG versus 66% controls had HIV-1 RNA levels <400
copies/ml (p =.026). Overall, 85% of patients with adherence >/=95%
but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml
(p =. 008). In multivariate analysis, variables significantly related
to adherence were having received a psychoeducative intervention (odds
ratio [OR], 6.58; p =.04), poor effort to take medication (OR, 5.38;
p =.03), and high self-perceived capacity to follow the regimen (OR,
13.76; p =.04). Self-reported adherence and drug plasma levels coincided
in 93% of cases. However, differences in adherence did not reach statistical
significance in the ITT analysis although a clear tendency toward benefit
was observed in EG.
CONCLUSIONS: Specific and maintained psychoeducative interventions
based on excellence on clinical practice are useful to keep high levels
of adherence as well as high levels of viral suppression. There is a
clear relation between high adherence levels and virologic success.
Assessment of certain specific variables related to adherence may be
helpful to monitor patient's compliance in the clinical setting. |
| Long-term impact of highly active antiretroviral
therapy on HIV-related health care costs.
Keiser P, Nassar N, Kvanli MB, Turner D, Smith JW, Skiest D.
The University of Texas Southwestern Medical Center at Dallas, and
Department of Veterans Affairs Medical Center, Dallas, Texas, USA. |
J Acquir Immune Defic Syndr 2001 May 1;27(1):14-9 Abstract
quote
CONTEXT: Highly active antiretroviral therapy (HAART) is associated
with decreased opportunistic infections, hospitalization, and HIV-related
health care costs over relatively short periods of time. We have previously
demonstrated that decreases in total HIV cost are proportional to penetration
of protease inhibitor therapy in our clinic.
OBJECTIVE: To determine the effects of HAART on HIV health care use
and costs over 44 months.
SETTING: A comprehensive HIV service within a Veterans Affairs Medical
Center.
DESIGN: A cost-effectiveness analysis of HAART.
MAIN OUTCOME MEASUREMENTS: The mean monthly number of hospital days,
infectious diseases clinic visits, emergency room visits, non-HIV-related
outpatient visits, inpatient costs, and antiretroviral treatment costs
per patient were determined by dividing these during the period from
January 1995 through June 1998 into four intervals. Viral load tests
were available from October 1996. Cost-effectiveness of HAART was evaluated
by determining the costs of achieving an undetectable viral load over
time.
RESULTS: Mean monthly hospitalization and associated inpatient costs
decreased and remained low 2 years after the introduction of protease
inhibitors (37 hospital days per 100 patients). Total cost decreased
from $1905 per patient per month during the first quarter to $1090 per
patient per month in the third quarter but increased to $1391 per patient
per month in the fourth quarter. Antiretroviral treatment costs increased
throughout the entire observation period from $79 per patient per month
to $518 per patient per month. Hospitalization costs decreased from
$1275 per patient per month in the first quarter to less than $500 per
patient per month in each of the third and fourth quarters. The percentage
of patients with a viral load <500 copies/mL increased from 21% in October
1996 to 47% in June of 1997 (p =.014). The cost of achieving an undetectable
viral load decreased from $4438 per patient per month to $2669 per patient
per month, but this trend did not reach statistical significance (p
=.18).
CONCLUSIONS: After an initial decrease, there was an increase in the
total monthly cost of caring for HIV patients. Cost increases were primarily
due to antiretroviral treatment costs, but these costs were offset by
a marked decrease in inpatient-related costs. Increases in costs were
not related to antiretroviral treatment failures as measured by the
proportion of patients with low or undetectable viral loads. The cost
of achieving an undetectable viral load remained stable despite increases
in the cost of procuring antiretroviral agents. |
| VACCINE |
|
| Replication-incompetent adenoviral vaccine vector
elicits effective anti-immunodeficiency-virus immunity.
Shiver JW, Fu TM, Chen L, Casimiro DR, Davies ME, Evans RK, Zhang
ZQ, Simon AJ, Trigona WL, Dubey SA, Huang L, Harris VA, Long RS, Liang
X, Handt L, Schleif WA, Zhu L, Freed DC, Persaud NV, Guan L, Punt KS,
Tang A, Chen M, Wilson KA, Collins KB, Heidecker GJ, Fernandez VR, Perry
HC, Joyce JG, Grimm KM, Cook JC, Keller PM, Kresock DS, Mach H, Troutman
RD, Isopi LA, Williams DM, Xu Z, Bohannon KE, Volkin DB, Montefiori
DC, Miura A, Krivulka GR, Lifton MA, Kuroda MJ, Schmitz JE, Letvin NL,
Caulfield MJ, Bett AJ, Youil R, Kaslow DC, Emini EA.
Merck Research Laboratories, West Point, Pennsylvania 19486, USA. |
Nature 2002 Jan 17;415(6869):331-5 Abstract quote
Recent studies of human immunodeficiency virus type 1 (HIV-1) infection
in humans and of simian immunodeficiency virus (SIV) in rhesus monkeys
have shown that resolution of the acute viral infection and control
of the subsequent persistent infection are mediated by the antiviral
cellular immune response.
We comparatively assessed several vaccine vector delivery systems-three
formulations of a plasmid DNA vector, the modified vaccinia Ankara (MVA)
virus, and a replication incompetent adenovirus type 5 (Ad5) vector-expressing
the SIV gag protein for their ability to elicit such immune responses
in monkeys. The vaccines were tested either as a single modality or
in combined modality regimens.
Here we show that the most effective responses were elicited by a replication-incompetent
Ad5 vector, used either alone or as a booster inoculation after priming
with a DNA vector. After challenge with a pathogenic HIV-SIV hybrid
virus (SHIV), the animals immunized with Ad5 vector exhibited the most
pronounced attenuation of the virus infection.
The replication-defective adenovirus is a promising vaccine vector
for development of an HIV-1 vaccine. |
|
Eventual AIDS vaccine failure in a rhesus monkey by viral escape
from cytotoxic T lymphocytes.
Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl
FW, Krivulka GR, Beaudry K, Lifton MA, Gorgone DA, Montefiori DC, Lewis
MG, Wolinsky SM, Letvin NL.
Department of Medicine, Harvard Medical School, Beth Israel Deaconess
Medical Center, Research East Room 113, 330 Brookline Avenue, Boston,
Massachusetts 02215, USA. |
Nature 2002 Jan 17;415(6869):335-9 Abstract quote
Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited
by candidate AIDS vaccines have recently been shown to control viral
replication and prevent clinical disease progression after pathogenic
viral challenges in rhesus monkeys.
Here we show that viral escape from CTL recognition can result in the
eventual failure of this partial immune protection. Viral mutations
that escape from CTL recognition have been previously described in humans
infected with human immunodeficiency virus (HIV) and monkeys infected
with simian immunodeficiency virus (SIV). In a cohort of rhesus monkeys
that were vaccinated and subsequently infected with a pathogenic hybrid
simian-human immunodeficiency virus (SHIV), the frequency of viral sequence
mutations within CTL epitopes correlated with the level of viral replication.
A single nucleotide mutation within an immunodominant Gag CTL epitope
in an animal with undetectable plasma viral RNA resulted in viral escape
from CTLs, a burst of viral replication, clinical disease progression,
and death from AIDS-related complications.
These data indicate that viral escape from CTL recognition may be a
major limitation of the CTL-based AIDS vaccines that are likely to be
administered to large human populations over the next several years. |
| AIDSVAX |
|
AIDSVAX. VaxGen.
Billich A.
Norvartis Research Institute, PO Box 80, Brunner Strasse 59,
1235 Vienna, Austria. |
Curr Opin Investig Drugs 2001 Sep;2(9):1203-8 Abstract quote
AIDSVAX, a bivalent vaccine consisting of a preparation of recombinant
gp120 from two types of HIV, is being developed by VaxGen for the potential
prevention of HIV infection [274573]. Two versions of the vaccine are
in phase III trials: AIDSVAX B/E, in phase III trials in Thailand, stimulates
production of antibodies to HIV subtypes common to South and Southeast
Asia, and countries of the Pacific Rim; and AIDSVAX B/B, in phase III
trials in the US and Europe, stimulates production of antibodies to
HIV subtypes that are found in the Americas, Europe, the Caribbean and
Australia [314365], [397186]. The bivalent vaccine is based on an earlier
monovalent vaccine, MNrgp120 (Genetech Inc/VaxGen Inc) [274573], [356845].
In April 2001, the independent data and safety monitoring board (DSMB)
reviewed data from the trials and indicated that the vaccine appeared
safe and that the trials were being conducted appropriately. VaxGen
has disclosed that an average of 95% of volunteers continue to participate
in the phase III trials. The DSMB was scheduled to conduct its review
in November 2001, to examine the efficacy of AIDSVAX in the prevention
of HIV infection. VaxGen would halt the trial early if the interim analysis
shows the vaccine to be effective. The company would then begin the
process of applying for regulatory approval.
If the interim analysis proves inconclusive, the trial would proceed
to its scheduled conclusion in the fourth quarter of 2002 [386730],
[405696]. In August 1998, a collaborative research agreement was signed
with the National Institute of Allergy and Infectious Diseases (NIAID).
This includes research on combinations of AIDSVAX and other NIAID vaccines
and research for new formulations suitable for developing nations [295166].
|
|
Advancing AIDSVAX to phase 3. Safety, immunogenicity, and plans
for phase 3.
Francis DP, Gregory T, McElrath MJ, Belshe RB, Gorse GJ, Migasena
S, Kitayaporn D, Pitisuttitham P, Matthews T, Schwartz DH, Berman PW.
VaxGen, Inc., South San Francisco, California 94080, USA |
AIDS Res Hum Retroviruses 1998 Oct;14 Suppl 3:S325-31 Abstract quote
AIDSVAX (VaxGen, Inc., South San Francisco, CA), a possible vaccine
to protect against human immunodeficiency virus type 1 (HIV-1) infection,
is being tested for efficacy in phase 3 studies. It has been tested
for potential efficacy in chimpanzees, and tested for safety and immunogenicity
in human clinical studies. Four candidate vaccines, each with a different
envelope protein antigen or combination of antigens, have been produced
in alum formulations. In both design and clinical testing, AIDSVAX has
an excellent safety profile. Because these highly purified proteins
were prepared using recombinant DNA technology, there is no possibility
of these vaccines causing HIV infection.
Having been administered to over 1200 people, the only side effects
attributable to AIDSVAX have been local pain and inflammation at the
injection site. After immunization, essentially all recipients developed
a robust antibody response, including binding and neutralizing antibodies.
The neutralizing antibodies peaked after a 12-month boost. Excellent
memory is induced.
Two phase 3 trials of two bivalent formulations will evaluate their
efficacy. One trial will use a bivalent subtype B formulation. This
trial in North America will involve 5000 men who have sex with men and
heterosexual women at high risk. The other study will use a bivalent
subtype B/subtype E formulation. This trial in Thailand and will involve
2500 intravenous drug users. Both studies will be randomized, double-blinded
and placebo controlled. The volunteers will be followed for 3 years.
The end points of the studies are infection, as defined by seroconversion
to standard diagnostic tests, and viral load, as defined by commercial
polymerase chain reaction (PCR) tests.
|
