IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis

Abstract

Background Combination antiretroviral treatment (cART) cannot eradicate HIV-1 from the body due to the establishment of persisting viral reservoirs which are not affected by therapy and reinitiate new rounds of HIV-1 replication after treatment interruption. These HIV-1 reservoirs mainly comprise long-lived resting memory CD4+ T cells and are established early after infection. There is a high variation in the size of these viral reservoirs among virally suppressed individuals. Identification of host factors that contribute to or can explain this observed variation could open avenues for new HIV-1 treatment strategies. Methods In this study, we conducted a genome-wide quantitative trait locus (QTL) analysis to probe functionally relevant genetic variants linked to levels of cell-associated (CA) HIV-1 DNA, CA HIV-1 RNA, and RNA:DNA ratio in CD4+ T cells isolated from blood from a cohort of 207 (Caucasian) people living with HIV-1 (PLHIV) on long-term suppressive antiretroviral treatment (median = 6.6 years). CA HIV-1 DNA and CA HIV-1 RNA levels were measured with corresponding droplet digital PCR (ddPCR) assays, and genotype information of 522,455 single-nucleotide variants was retrieved via the Infinium Global Screening array platform. Results The analysis resulted in one significant association with CA HIV-1 DNA (rs2613996, P < 5 × 10−8) and two suggestive associations with RNA:DNA ratio (rs7113204 and rs7817589, P < 5 × 10−7). Then, we prioritized PTDSS2, IRF7, RNH1, and DEAF1 as potential HIV-1 reservoir modifiers and validated that higher expressions of IRF7 and RNH1 were accompanied by rs7113204-G. Moreover, RNA:DNA ratio, indicating relative HIV-1 transcription activity, was lower in PLHIV carrying this variant. Conclusions The presented data suggests that the amount of CA HIV-1 DNA and RNA:DNA ratio can be influenced through PTDSS2, RNH1, and IRF7 that were anchored by our genome-wide association analysis. Further, these observations reveal potential host genetic factors affecting the size and transcriptional activity of HIV-1 reservoirs and could indicate new targets for HIV-1 therapeutic strategies.

Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

“…The second analysis demonstrated that there were no statistically significantly SNPs by "possible partial controller" status, in association with HIV reservoir size. Interestingly, several of the top (non-significant) SNPs identified from within the "possible partial controller" group were in or within 50 kb of immunologically relevant genes (Table S9), such as BRINP1, SNX29, IL1RAPL2, MX1, NFATC3, RIPK2, MASP2, TRIM6-TRIM34, HLA-A, and RNH1, the latter of which was reported as the top hit SNP from a recent genomewide association studiy of HIV reservoir size, as noted above (24). Finally, we only measured the peripheral CD4+ T cell reservoir, not the tissue reservoir, where the majority of HIV persists during treatment (107).…”

“…Therefore, in order to identify host genetic variation associated with the HIV reservoir size, we performed custom whole exome sequencing and HLA typing among HIV noncontrollers, including a range of individuals treated during "early" (within 6 months) and "later" (after 6 months) of HIV infection from the University of California San Francisco SCOPE and Options cohorts. Our study adds to two recent host genetic studies of the HIV reservoir (23,24), one of which was published concurrently to ours (24). The first (23) evaluated 797 HIV-infected acute-and chronic-treated individuals from the Swiss Cohort Study, of which 194 had whole exome sequencing performed but observed no association between genetic variants (including HLA or CCR5∆32) and reservoir size.…”

“…The study also imputed HLA alleles (from genotypes), rather than performed direct HLA typing, and it is unclear if the study adjusted for timing of ART initiation as a covariate in the modeling. The second (24) study was published concurrently with our own and included 207 chronic-treated individuals. GWAS microarray, rather than genetic sequencing, was performed, but HIV total DNA and unspliced RNA were quantified from peripheral CD4+ T cells.…”

Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls

“…Lymphocytes and monocytes were identified by granularity and size. Lymphocytes were further characterized using CD4, CD8, CD45RA and CCR7 to identify CD4+ cells and CD8+ naïve (CD45RA+CCR7+), central memory (CM, CD45RA-CCR7+), effector memory cells (EM, CD45RA-CCR7-), effector memory cells expressing CD45RA (TEMRA, CD45RA+CCR7-) and the total pool of effector memory cells (TEM, CD45RA-/+CCR7-) (41, 42). In addition, CD4+ naive regulatory (nTreg, CD45RA+CD25+) and CD4+ memory regulatory (mTreg, CD45RA-CD25++) cell subsets were identified.…”

“…For the PLHIV cohort, the genotyping, imputation, and quality control were described previously (41). In addition, for the healthy individuals, the genotyping, imputation, and quality control were performed as in the previous study (42).…”