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Dryad

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size

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Nov 20, 2023 version files 30.28 MB

Abstract

The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). Most prior studies of host genetic predictors of HIV control have focused on “elite controllers,” rare individuals able to control virus in the absence of ART. However, there have been few genetic studies among ART-suppressed non-controllers, who make up the majority of people living with HIV (PLWH). We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 HIV+ ART-suppressed non-controllers. After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q=0.006), IL-1/NRLP3 inflammasome (q=0.008), and IL-10 (q=0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-a protein associations achieving statistical significance (p<0.05). Of note, plasma IL-10 was also significantly inversely associated with HIV DNA (p=0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. Further data are needed to validate these findings, including functional genomic studies, larger cohorts including underrepresented PLWH in research, and those including dedicated assays to measure the replication-competent HIV reservoir.