Host Variation in Type I Interferon Signaling Genes (MX1), CCR5{triangleup}32, and MHC Class I Alleles in Treated HIV+ Non-Controllers Predict Viral Reservoir Size

Abstract

ObjectivePrior genomewide association studies have identified variation in MHC Class I alleles and CCR5{Delta}32 as genetic predictors of viral control, especially in "elite" controllers, individuals who remain virally suppressed in the absence of therapy. DesignCross-sectional genomewide association study. MethodsWe analyzed custom whole exome sequencing and direct HLA typing from 202 ART-suppressed HIV+ non-controllers in relation to four measures of the peripheral CD4+ T cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression. ResultsPreviously reported "protective" host genetic mutations related to viral setpoint (e.g., among elite controllers) were found to predict smaller HIV reservoir size. The HLA "protective" B*57:01 was associated with significantly lower HIV usRNA (q=3.3x10-3), and among the largest subgroup, European ancestry individuals, the CCR5{Delta}32 deletion was associated with smaller HIV tDNA (p=4.3x10-3) and usRNA (p=8.7x10-3). In addition, genomewide analysis identified several SNPs in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q=0.02), and the direction of these associations paralleled MX1 gene eQTL expression. ConclusionsWe observed a significant association between previously reported "protective" MHC class I alleles and CCR5{Delta}32 with the HIV reservoir size in non-controllers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.