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1284. Study of Single Nucleotide Polymorphisms Associated with HIV-1 Set-Point Viral Load in Antiretroviral Therapy-Naive HIV-Positive Participants of the START Study

ABSTRACT: Abstract Background HIV-1 set-point viral load (SPVL) is predictive of disease progression and shows variability across HIV-1-positive (HIV+) persons. Various factors may influence SPVL including viral features, environmental exposure and host genetics. To identify single nucleotide polymorphisms (SNPs) associated with SPVL, we performed a genome-wide association study (GWAS) on a subset of participants from the Strategic Timing of AntiRetroviral Treatment (START) study covering a demographically diverse population. Methods. Consenting participants were antiretroviral therapy (ART)-naïve and SPVL was taken as log10(HIV RNA) at study entry. Genotypic data were generated on a custom content Affymetrix Axiom SNP array covering 770,558 probes. The Ensembl Gene database, assembly GRCh37.p13, was used for annotation. Principal component analysis (PCA) was used to identify population structures, and analysis of variance (ANOVA) was performed to detect associations between SNPs and SPVL. SNPs with zero variance or minor allele frequency (MAF) ?0.05 were removed. Results. Among the 2,544 participants, PCA showed distinct population structures with strong separation between black (n = 578) and nonblack (n = 1,966) participants, Figure 1. ANOVA was performed independently on both subsets. Two SNPs located in the Major Histocompatibility Complex (MHC) class I region of chromosome six reached genome-wide significance (P < 5 × 10–8) in the non-black population: rs4418214 (P = 1.74 × 10-10), and rs57989216 (P = 3.96 × 10–8), Figure 2. Two additional SNPs, rs9264942 (P = 5.99 × 10–8) and rs7356880 (P = 9.69 × 10–8), in the same region approached significance. The minor alleles of all four SNPs were associated with lower SPVL, Figure 3. While no SNPs reached genome-wide significance in the black group, we observed similar trends toward lower SPVL for both rs4418214 and rs57989216. Conclusion. In this study we confirm the association of a previously reported SNP (rs4418214) and identify a novel candidate SNP (rs57989216) associated with lower SPVL in a population of nonblack, ART-naïve HIV+ persons. Current findings suggest that the effects of these SNPs are consistent across race groups, but further studies are required to confirm this. Our results support previous findings that variation in the MHC class I region is a major host determinant of HIV-1 control. Disclosures D. D. Murray, Centre of Excellence for Health, Immunity and Infectious diseases (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark: Employee, Salary. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee.

SUBMITTER: Ekenberg C

PROVIDER: S-EPMC6252472 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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.

Project description:HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors. We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4+ cell counts >500 cells/mm3. Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV-positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm3, an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL, and high-density lipoprotein cholesterol of 41 mg/dL. Mean follow-up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow-up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low-density lipoprotein cholesterol and higher use of lipid-lowering therapy (1.2%; 95% CI, 0.1-2.2). Concurrent increases in high-density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high-density lipoprotein cholesterol ratio (95% CI, 0.1-0.2). Immediate ART resulted in 2.3% less BP-lowering therapy use (95% CI, 0.9-3.6), but there were no differences in new-onset hypertension or diabetes mellitus. Among HIV-positive persons with preserved immunity, immediate ART led to increases in total cholesterol and low-density lipoprotein cholesterol but also concurrent increases in high-density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant." URL: http://www.clinicaltrials.gov. Unique identifier: NCT00867048.

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1284. Study of Single Nucleotide Polymorphisms Associated with HIV-1 Set-Point Viral Load in Antiretroviral Therapy-Naive HIV-Positive Participants of the START Study

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