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The article reports on the utilization of mutual information in the measurement of the impact of multiple genetic factors on AIDS. The discovery of the 32-base-pair deletion in the CCR5 chemokine receptor gene and its effect on HIV-1 infection led to the identification of genetic factors affecting AIDS. The influence of causal factors on disease is usually measured by the attributable fraction statistic. It revealed that 13 genetic factors can explain nine percent of slow progression to AIDS.

Genetic resistance to infectious diseases is likely to involve a complex array of immune-response and other genes with variants that impose subtle but significant consequences on gene expression or protein function. We have gained considerable insight into the genetic determinants of HIV-1 disease, and the HLA class I genes appear to be highly influential in this regard. Numerous reports have identified a role for HLA genotype in AIDS outcomes, implicating many HLA alleles in various aspects of HIV disease. Here we review the HLA associations with progression to AIDS that have been consistently affirmed and discuss the underlying mechanisms behind some of these associations based on functional studies of immune cell recognition. [ABSTRACT FROM AUTHOR]

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States-African American or United States-European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population. [ABSTRACT FROM AUTHOR]

Background. To date, onlymutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10-5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10-8. Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIV Fca ) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIV Ple ) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIV Ple subtypes, the data suggest that FIV Ple subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations. [Copyright &y& Elsevier]

Background. High-throughput genome-wide techniques have facilitated the identification of previously unknown host proteins involved in cellular human immunodeficiency virus (HIV) infection. Recently, 3 independent studies have used small interfering RNA technology to silence each gene in the human genome to determine the importance of each in HIV infection. Genes conferring a significant effect were termed HIV-dependency factors (HDFs). Methods. We assembled high-density panels of 6380 single-nucleotide polymorphisms (SNPs) in 278 HDF genes and tested for genotype associations with HIV infection and AIDS progression in 1633 individuals from clinical AIDS cohorts. Results. After statistical correction for multiple tests, significant associations with HIV acquisition were found for SNPs in 2 genes, NCOR2 and IDH1. Weaker associations with AIDS progression were revealed for SNPs within the TM9SF2 and EGFR genes. Conclusions. This study independently verifies the influence of NCOR2 and IDH1 on HIV transmission, and its findings suggest that variation in these genes affects susceptibility to HIV infection in exposed individuals. [ABSTRACT FROM AUTHOR]

Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl- CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis. [ABSTRACT FROM AUTHOR]

The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans. [ABSTRACT FROM AUTHOR]

The article studies the influence of AIDS restriction genes and haplotypes of the CCR5 P1 promoter and RANTES variants among HIV-1 infected patients on highly active antiretroviral therapy in the Multicenter AIDS Cohort Study and the Multicenter Hemophilia Cohort Study. It examines a range of genes that were predicted to influence HAART through various interactions with the HIV life cycle and drug metabolism.

Background: Feline immunodeficiency virus (FIV) naturally infects multiple species of cat and is related to human immunodeficiency virus in humans. FIV infection causes AIDS-like disease and mortality in the domestic cat (Felis catus) and serves as a natural model for HIV infection in humans. In African lions (Panthera leo) and other exotic felid species, disease etiology introduced by FIV infection are less clear, but recent studies indicate that FIV causes moderate to severe CD4 depletion. Results: In this study, comparative genomic methods are used to evaluate the full proviral genome of two geographically distinct FIV subtypes isolated from free-ranging lions. Genome organization of FIVPle subtype B (9891 bp) from lions in the Serengeti National Park in Tanzania and FIVPle subtype E (9899 bp) isolated from lions in the Okavango Delta in Botswana, both resemble FIV genome sequence from puma, Pallas cat and domestic cat across 5' LTR, gag, pol, vif, orfA, env, rev and 3'LTR regions. Comparative analyses of available full-length FIV consisting of subtypes A, B and C from FIVFca, Pallas cat FIVOma and two puma FIVPco subtypes A and B recapitulate the species-specific monophyly of FIV marked by high levels of genetic diversity both within and between species. Across all FIVPle gene regions except env, lion subtypes B and E are monophyletic, and marginally more similar to Pallas cat FIVOma than to other FIV. Sequence analyses indicate the SU and TM regions of env vary substantially between subtypes, with FIVPle subtype E more related to domestic cat FIVFca than to FIVPle subtype B and FIVOma likely reflecting recombination between strains in the wild. Conclusion: This study demonstrates the necessity of whole-genome analysis to complement population/ gene-based studies, which are of limited utility in uncovering complex events such as recombination that may lead to functional differences in virulence and pathogenicity. These full-length lion lentiviruses are integral to the advancement of comparative genomics of human pathogens, as well as emerging disease in wild populations of endangered species. [ABSTRACT FROM AUTHOR]

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection. [ABSTRACT FROM AUTHOR]

Abstract: TRIM5α acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5α on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5α 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5α 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5α R136 protein. The 43Y variant of TRIM5α was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts. [Copyright &y& Elsevier]

Background. Some individuals are readily infected with low human immunodeficiency virus type 1 (HIV-1) exposure, whereas others appear less susceptible, suggesting that host genetics plays a role in the viral entry pathway. The matched case-control study design with measured risk exposures provides an avenue for discovering genes involved in susceptibility to infection. Methods. We conducted a nested case-control study of African Americans (266 HIV-1 seroconverter cases and 532 seronegative controls from the AIDS Link to Intravenous Experience cohort), to examine the association between 50 single-nucleotide polymorphisms (SNPs) in 9 candidate genes (CCR5, CCR2, RANTES, MIPIA, MCP2, ILl0, IFNG, MCSF, and 1L2) and susceptibility to HIV-1 infection. To account for differential exposure propensities, risk behavior self-reported during semiannual visits was used to estimate a standardized cumulative risk exposure (SGRE). Individual SNPs were evaluated using conditional logistic-regression models, and the inferred haplotypes were assessed in the haplotype trend regression analyses after adjusting for age and SGRE. Results. Four SNPs (CCR2-V641, CCR5- 2459, MIPJA+954, and 1L2+3896) and specific haplotypes in the 1L2 and CCR2/CCR5 regions were significantly associated with HIV-1 infection susceptibility in different genetic models. Conclusions. Our results suggest that genetic variants in associated host genes may play an important role in susceptibility to HIV-1 infection. [ABSTRACT FROM AUTHOR]

This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P = .009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5Δ32 and CCR2- 64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4- tropic viruses (P = .012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease. [ABSTRACT FROM AUTHOR]

There is considerable debate about the fundamental mechanisms that underlie and restrict acquisition of human immunodeficiency virus type 1 (HIV-1) infection. In light of recent studies demonstrating the ability of C type lectins to facilitate infection with HIV-1, we explored the potential relationship between polymorphisms in the DC-SIGN promoter and risk for acquisition of HIV-1 according to route of infection. Using samples obtained from 1,611 European-American participants at risk for parenteral (n = 713) or mucosal (n = 898) infection, we identified single-nucleotide polymorphisms in the DC-SIGN promoter using single-strand conformation polymorphism. Individuals at risk for parenterally acquired infection who had -336C were more susceptible to infection than were persons with -336T (odds ratio = 1.87, P = 0.001). This association was not observed in those at risk for mucosally acquired infection. A potential role for DC-SIGN specific to systemic acquisition and dissemination of infection is suggested. [ABSTRACT FROM AUTHOR]

Reports the relative contributions to AIDS progression of three promoter haplotypes of CCR2-CCR5. Comparison of the rapid progression with a seroconverter control group including intermediate progressors to AIDS; Data indicating that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.

Discusses the lack of associations between HLA class II alleles and resistance to HIV-1 infection among white, non-Hispanic, gay men. HLA class II alleles were molecularly typed for 100 high-risk seronegative men; Transporter associated with antigen presentation 2; Linkage disequilibrium with some HLA class II alleles.

A polymorphism, 3179G/T, in the promoter of the interferon (IFN)-γ gene (IFNG) confers differential tumor necrosis factor-α (TNF-α) inducibility to the IFNG promoter. The rarer allele, 3179T, but not 3179G, is inducible by TNF-α. We investigated the effects of IFNG 3179G/T on AIDS pathogenesis. In 298 African American human immunodeficiency virus (HIV)-1 seroconverters, the IFNG 3179G/T genotype was associated with accelerated progression to CD4<200 and AIDS-1993, a finding suggesting that IFNG 3179T is a risk factor for AIDS progression, as measured by CD4 cell count. It is possible that increased IFN-γ production induced by TNF-α when 3179T is present causes CD4 cell depletion by apoptosis. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) is a pleiotropic cytokine produced primarily by activated CD4+ T lymphocytes, mast cells, and basophils. It modulates the functions of a variety of cell types involved with the immune response. This cytokine differentially regulates two major HIV-1 coreceptors and activates viral expression, and is thus a reasonable candidate gene for analyses in HIV-1/AIDS cohort studies. Population genetic variation in five single nucleotide polymorphisms (SNPs) in the 5′ region of the IL-4 gene was assessed in five racial groups. Neutrality tests reveal that the populations are evolving in accord with the infinite-sites model. However, coalescent simulations suggest greater haplotype diversity among African Americans than expected. This increased variation is presumably attributable to recombination or gene conversion. Genetic epidemiological analyses were conducted among European American and African American participants enrolled in five USA-based HIV-1/AIDS cohorts. One SNP, -589T, known to influence IL-4 transcription was previously shown to be associated with HIV-1/AIDS in both Japanese and French populations. Present analyses failed to identify any significant associations with HIV-1 infection or progression to AIDS. [ABSTRACT FROM AUTHOR]

Examines the relationship of human leukocyte antigen (HLA) class I and transporter associated with antigen processing genes with resistance to HIV-1 infection. Effect of the presence of the subgroup alleles; Possibility for the differential preferences for amino acids at the C terminus to influence peptide-binding capacity.

Seven long-term nonprogressors (LTNPs) have been identified in a cohort of 128 human immunodeficiency virus (HIV)-1infected individuals with hemophilia. Studies included quantitation of virus by polymerase chain reaction, characterization of primary virus isolates in vitro, analysis of lymphocyte surface markers, and measurement of virus-specific cytotoxic T lymphocytes (CTLs). Viruses of LTNPs exhibited slow growth in vivo and in vitro. LTNPs had expansion of CD8 T cells with increased expression of HLA-DR. Intermittent HIV-1-specific CTL effector activity was detected in freshly isolated peripheral blood mononuclear cells of most LTNPs. CTL precursor frequencies were higher in LTNPs than in patients with progressive disease. Virus antigen-specific lymphoproliferation was vigorous in some LTNPs. Thus, LTNPs in this cohort have maintained remarkably low virus burdens and vigorous HIV-1-specific cell-mediated immunity over a 15-year period. The presence of expanded, activated CD8 T cells with cytotoxic effector function in the peripheral blood suggests ongoing viral replication. [ABSTRACT FROM AUTHOR]

The article presents a study on the effect of host genetics on human immunodeficiency virus neuroretinal disorder (HIV-NRD) in patients with AIDS. It notes the loss of contrast sensitivity that is sufficient to impair reading speed. It mentions the validated AIDS restriction gene variants in evaluating the effect of host genes on HIV-NRD which has been implicated to influence HIV-1 infection, AIDS progression, therapy response, and antiviral drug metabolism.

An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of previously reported host genetics factors that influence cytomegalovirus (CMV) retinitis incidence, progression to acquired immune deficiency syndrome (AIDS), and efficacy of highly active antiretroviral therapy (HAART) for mortality, retinitis progression, and retinal detachment in patients with CMV retinitis and AIDS in the era of HAART. Design: Prospective, multicenter, observational study. Methods: Cox proportional hazards model based genetic association tests examined the influence of IL-10R1_S420L, CCR5-Δ32, CCR2-V64I, CCR5 promoter, and SDF-3′A polymorphisms among patients with mortality, retinitis progression, and retinal detachment. Participants were 203 European-American and 117 African-American patients with AIDS and CMV retinitis. Results: European-American patients with the CCR5 +.P1.+ promoter haplotype showed increased risk for mortality (hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.00-3.40; P = .05). Although the same haplotype also trended for increased risk for mortality in African-American patients, the result was not significant (HR = 2.28; 95% CI: 0.93-5.60; P = .07). However, this haplotype was associated with faster retinitis progression in African Americans (HR = 5.22; 95% CI: 1.54-17.71; P = .007). Increased risk of retinitis progression was also evident for African-American patients with the SDF1-3′A variant (HR = 3.89; 95% CI: 1.42-10.60; P = .008). In addition, the SDF1-3′A variant increased the retinal detachment risk in this patient group (HR = 3.05; 95% CI: 1.01-9.16; P = .05). Conclusion: Besides overall immune health, host genetic factors influence mortality, retinitis progression, and retinal detachment in patients with AIDS and CMV retinitis that are receiving HAART. [ABSTRACT FROM AUTHOR]