Dataset Information

Host genetics and HIV-1 viral load set-point in African-Americans.

ABSTRACT: OBJECTIVE:In a recent genome-wide association study of HIV-1-infected individuals in the Euro-CHAVI cohort, viral load set-point was strongly associated with genotypes defined by two single nucleotide polymorphisms (SNPs) (rs9264942 and rs2395029) within the human major histocompatibility complex (MHC) region on chromosome 6. We attempted to confirm this finding in African-Americans and to address whether these SNPs are in linkage disequilibrium with human leukocyte antigen (HLA) class I alleles that mediate innate and adaptive immunity. DESIGN:Our analyses relied on 121 African-American adolescents with chronic HIV-1 infection and quarterly immunological and virological outcome measures in the absence of therapy. METHODS:PCR-based techniques were used to genotype two SNPs along with HLA class I alleles. Their associations with HIV-1 viral load set-point and longitudinal CD4+ and CD8+CD38+ T cell counts were tested in univariate and multivariable models. RESULTS:The CC genotype at rs9264942 was associated with reduced viral load, but not with immunological outcomes or category of disease control. Consistent associations of favorable virologic outcomes were observed with B*57 (mostly B*5703) but not with rs2395029G allele at the HCP5 locus, which is in absolute linkage disequilibrium with B*5701 (in individuals of European descent), and not B*5703. CONCLUSION:Although rs9264942 and B*57 (but not rs2395029G) are clearly associated with control of viral load set-point among African-Americans, fine-mapping of MHC SNPs in populations of African and European descent should help reveal the causative variants and the underlying functional mechanisms.

SUBMITTER: Shrestha S

PROVIDER: S-EPMC2663898 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Host genetics and HIV-1 viral load set-point in African-Americans.

Shrestha Sadeep S Aissani Brahim B Song Wei W Wilson Craig M CM Kaslow Richard A RA Tang Jianming J

AIDS (London, England) 20090301 6

<h4>Objective</h4>In a recent genome-wide association study of HIV-1-infected individuals in the Euro-CHAVI cohort, viral load set-point was strongly associated with genotypes defined by two single nucleotide polymorphisms (SNPs) (rs9264942 and rs2395029) within the human major histocompatibility complex (MHC) region on chromosome 6. We attempted to confirm this finding in African-Americans and to address whether these SNPs are in linkage disequilibrium with human leukocyte antigen (HLA) class I ...[more]

PMID: 19276793

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Project description:HIV viral load (VL) predicts both transmission potential and rate of disease progression. For reasons that are still not fully understood, the set point viral load (SPVL) established after acute infection varies across individuals and populations. Previous studies have suggested that population mean SPVL (MSPVL) has evolved near an optimum that reflects a trade-off between transmissibility and host survival. Sexual network structures affect rates of potential exposure during different within-host phases of infection marked by different transmission probabilities, and thus affect the number and timing of transmission events. These structures include relational concurrency, which has been argued to explain key differences in HIV burden across populations. We hypothesize that concurrency will alter the fitness landscape for SPVL in ways that differ from other network features whose impacts accrue at other times during infection. To quantitatively test this hypothesis, we developed a dynamic, stochastic, data-driven network model of HIV transmission, and evolution to assess the impact of key sexual network phenomena on MSPVL evolution. Experiments were repeated in sensitivity runs that made different assumptions about transmissibility during acute infection, SPVL heritability, and the functional form of the relationship between VL and transmissibility. For our main transmission model, scenarios yielded MSPVLs ranging from 4.4 to 4.75 log10 copies/ml, covering much of the observed empirical range. MSPVL evolved to be higher in populations with high concurrency and shorter relational durations, with values varying over a clinically significant range. In linear regression analyses on these and other predictors, main effects were significant (P < 0.05), as were interaction terms, indicating that effects are interdependent. We also noted a strong correlation between two key emergent properties measured at the end of the simulations-MSPVL and HIV prevalence-most clearly for phenomena that affect transmission networks early in infection. Controlling for prevalence, high concurrency yielded higher MSPVL than other network phenomena. Interestingly, we observed lower prevalence in runs in which SPVL heritability was zero, indicating the potential for viral evolution to exacerbate disease burden over time. Future efforts to understand empirical variation in MSPVL should consider local HIV burden and basic sexual behavioral and network structure.

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Dataset Information

Host genetics and HIV-1 viral load set-point in African-Americans.

Publications

Host genetics and HIV-1 viral load set-point in African-Americans.

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