Host Variation in Interferon, MHC Class I, Glycosylation, and Viral Transcription Genes Predict HIV Persistence

Background: Prior host genomewide association studies have failed to observe an association with the HIV reservoir. Methods: Custom whole exome sequencing and direct HLA typing were performed from 202 HIV+ ART-suppressed individuals and associated with 4 measures of the circulating CD4+ T cell reservoir: total DNA, unspliced (us)RNA, RNA/DNA, and intact DNA. Common variant, gene-based, and HLA analyses were performed using linear mixed models adjusted for sex, timing of ART initiation, nadir CD4 count, input cell count, and ancestry. Results: HIV total DNA was associated with variants in genes involved in type I interferon (MX1, PPP1CB, DDX3X) and MHC class I peptide recognition (LRMP), while HIV usRNA was associated with a variant related to lymphocyte lymph node migration (PLVAP; this SNP was also <30kb from BST2, which encodes tetherin, an HIV host restriction factor). Gene-based analyses demonstrated significant associations with type I interferon (intact DNA), glycosylation (total DNA), and retroviral transcription (usRNA). HLA "protective" B*57:01 and "risk" C*07 alleles, as well as CCR5Δ32, were associated with HIV usRNA and total DNA, but not intact DNA. Conclusions: Host genetic variation in type I interferon, MHC class I, glycosylation, residual viral transcription, and lymphocyte lymph node migration may influence the circulating HIV CD4+ T cell reservoir.