A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1

Center for Population Genomics and Pharmacogenetics, Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
Science (Impact Factor: 33.61). 09/2007; 317(5840):944-7. DOI: 10.1126/science.1143767
Source: PubMed


Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort
to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain
nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of
these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)–B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase
I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious

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    • "Our results suggest that RNF39 expression knockdown inhibits HIV-1 expression, suggesting that RNF39 is required for viral replication. Genome-wide association studies (GWASs) revealed that human genetic variations, especially in genes located in the MHC region are involved in the control of HIV viral load, CD4 count, or the disease clinical course [11,16]. A few studies revealed that human genetic variations, especially genes located in the MHC region, close to RNF39, were associated with the control of HIV viral load, CD4 count, and/or the disease clinical course, but the results were still inconsistent [11,12,16,17]. "
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    ABSTRACT: Background The human immunodeficiency virus (HIV-1) exploits host proteins to complete its life cycle. Genome-wide siRNA approaches suggested that host proteins affect HIV-1 replication. However, the results barely overlapped. RING finger protein 39 (RNF39) has been identified from genome-wide association studies. However, its function during HIV-1 replication remains unclear. Methods and results We investigated the relationship between common RNF39 genetic variants and HIV-1 viral loads. The effect of RNF39 protein knockdown or overexpression on HIV-1 replication was then investigated in different cell lines. Two genetic variants were associated with HIV-1 viral loads. Patients with the ht1-GG/GG haplotype presented lower RNF39 expression levels and lower HIV-1 viral load. RNF39 knockdown inhibited HIV-1 expression. Conclusions RNF39 protein may be involved in HIV-1 replication as observed in genetic studies on patients with HIV-1 and in in vitro cell cultures.
    Cell and Bioscience 08/2014; 4(1):40. DOI:10.1186/2045-3701-4-40 · 3.63 Impact Factor
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    • "Predictors of set-point vl range from viral characteristics (e.g., subtypes and replicative capacity) (Prentice et al. 2014a; Prince et al. 2012; Yue et al. 2013) to host genotypes (Qtls) that govern innate and adaptive immune responses (apps et al. 2013; Fellay et al. 2009; leslie et al. 2010; Prentice and tang 2012). Depending on the study population and definition of set-point vl (single or multiple measurements), the proportion of vl variance explained by any single host or viral factor is often less than 4 % (Fellay et al. 2007; Prentice et al. 2014a; Yue et al. 2013). the most promising model that incorporates genetic and non-genetic features of epidemiologically linked HIv-1 transmission pairs (source and recipient partners) can account for nearly 37 % of early set-point vl variance (Yue et al. 2013). "
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    ABSTRACT: Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of "missing heritability" in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.
    Human Genetics 06/2014; 133(9). DOI:10.1007/s00439-014-1465-x · 4.82 Impact Factor
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    • "Recently Fellay et al. conducted a whole-genome association study to identify the host factor associated with control of HIV-1. In this study they identified two distinct polymorphisms associated with HLA loci B and C [24]. Surprisingly, almost all HLA class I polymorphisms were found to occur in those residues that belong to peptide-binding groove of these molecules thereby determining the epitopes that bind to each HLA molecule [25]. "
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    ABSTRACT: Human immunodeficiency virus (HIV) possesses a major threat to the human life largely due to the unavailability of an efficacious vaccine and poor access to the antiretroviral drugs against this deadly virus. High mutation rate in the viral genome underlying the antigenic variability of the viral proteome is the major hindrance as far as the antibody based vaccine development is concerned. Although the exact mechanism by which CTL epitopes and the restricting HLA alleles mediate their action towards slow disease progression is still not clear, the important CTL restricted epitopes for controlling viral infections can be utilized in future vaccine design. This study was designed for the characterization the HIV-1 optimal CTL epitopes and their corresponding HLA alleles. CTL epitope cluster distribution analysis revealed only two HIV-1 proteins, namely, Nef and Gag, which have significant cluster forming capacity. We have found the role of specific HLA supertypes such as HLA B∗07, HLA B∗58, and HLA A∗03 in selecting the hydrophobic and conserved amino acid positions within Nef and Gag proteins, to be presented as epitopes. The analyses revealed that the clusters of optimal epitopes for Nef and p24 proteins of HIV-1 could potentially serve as a source of vaccine.
    Advances in Virology 03/2014; 2014:321974. DOI:10.1155/2014/321974
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