Association Between Single-Nucleotide Polymorphisms in HLA Alleles and Human Immunodeficiency Virus Type 1 Viral Load in Demographically Diverse, Antiretroviral Therapy-Naive Participants From the Strategic Timing of AntiRetroviral Treatment Trial

Abstract

The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy-naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool.

Keywords: GWAS; HIV-1; HLA; genome-wide association study; host genetics; viral load.

Figure 1.

Single-nucleotide polymorphisms (SNPs) associated with viral load. The Manhattan plot shows the association between SNPs and log₁₀ viral load in the cohort. Each SNP is represented by a point and plotted by chromosomal location (x-axis), and –log₁₀(P-value) per SNP is shown on the y-axis. Genome-wide significance is indicated by the horizontal red line (P-value < 5 × 10^–8).

Figure 2.

Summary of genome-wide significant major histocompatibility complex class I (MHC I) single-nucleotide polymorphisms (SNPs) associated with viral load. A, The location of the 5 significant SNPs in the MHC I region of chromosome 6 and a heatmap of linkage disequilibrium highlighting local structures of SNPs in linkage disequilibrium with one another. The positions of the top 5 SNPs are shown as blue points. B, Violin plots of viral load distributions for each of the 5 SNPs and their different genotypes. Abbreviations: alt/alt, homozygotes for the alternate allele; kb, kilobase; ref/alt, heterozygotes; ref/ref, homozygotes for the reference allele; VL, viral load.

Figure 3.

Effect sizes (including 95% confidence intervals [CIs]) of significant single-nucleotide polymorphisms (SNPs) associated with viral load. The effect size (beta) is the difference in log₁₀ viral load per additional alternate allele. The covariates included in the regression analysis were the leading 4 eigenvectors and sex.