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 CCR5 Δ 32 . 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. ### Competing Interest Statement The authors have declared no competing interest.