Differences in expression of tumor suppressor, innate immune, inflammasome, and potassium/gap junction channel host genes significantly predict viral reservoir size during treated HIV infection

Abstract

The major barrier to an HIV cure is the persistence of infected cells that evade host immune surveillance despite effective antiretroviral therapy (ART). Most prior host genetic HIV studies have focused on identifying DNA polymorphisms (e.g., CCR5Δ32, MHC class I alleles) associated with viral load among untreated "elite controllers" (~1% of HIV+ individuals who are able to control virus without ART). However, there have been few studies evaluating host genetic predictors of viral control for the majority of people living with HIV (PLWH) on ART. We performed host RNA sequencing and HIV reservoir quantification (total DNA, unspliced RNA, intact DNA) from peripheral CD4+ T cells from 191 HIV+ ART-suppressed non-controllers. Multivariate models included covariates for timing of ART initiation, nadir CD4+ count, age, sex, and ancestry. Lower HIV total DNA (an estimate of the total reservoir) was associated with upregulation of tumor suppressor genes NBL1 (q=0.012) and P3H3 (q=0.012). Higher HIV unspliced RNA (an estimate of residual HIV transcription) was associated with downregulation of several host genes involving inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10) and innate immune (TLR7) signaling, as well as novel associations with potassium (KCNJ2) and gap junction (GJB2) channels, all q<0.05. Gene set enrichment analyses identified significant associations with TLR4/microbial translocation (q=0.006), IL-1b/NRLP3 inflammasome (q=0.008), and IL-10 (q=0.037) signaling. HIV intact DNA (an estimate of the "replication-competent" reservoir) demonstrated trends with thrombin degradation (PLGLB1) and glucose metabolism (AGL) genes, but data were (HIV intact DNA detected in only 42% of participants). Our findings demonstrate that among treated PLWH, that inflammation, innate immune responses, bacterial translocation, and tumor suppression/cell proliferation host signaling play a key role in the maintenance of the HIV reservoir during ART. Further data are needed to validate these findings, including functional genomic studies, and expanded epidemiologic studies in female, non-European cohorts.

Targeting Inflammasome Activation in Viral Infection: A Therapeutic Solution?

“…NLRP3 inflammasome activated in HIV-infected cells and associated production of ROS induces pyroptosis in CD4+ T cells, which is also one of the major reasons for the decreased efficacy of anti-HIV regimens in chronic infection [ 54 ]. Gene-set enrichment analysis of RNA from peripheral CD4+ T cells of antiretroviral therapy-treated HIV patients reveals that activation of the NLRP3 inflammasome is closely related to the maintenance of the HIV infection reservoir during treatment [ 55 ]. Treatment with the NLRP3 inhibitor MCC950 markedly reduces death of HIV-infected peripheral blood CD4+ T cells [ 54 ].…”

Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial

“…Furthermore, we now observe a synergistic effect of low CD4 nadir and more recent initiation of ART for increased CHIP prevalence. The residual inflammation demonstrated in virally suppressed PWH has long-term health implications 29 , 30 and has recently been demonstrated to be affected by host tumor suppressor, innate immune, and inflammasome responses. Resistance to chronic inflammation has been demonstrated to be a critical element of clonal selection and survival advantage in CHIP.…”

“… 34 The residual inflammation demonstrated in virally suppressed PWH has long-term health implications 35 , 29 and has recently been demonstrated to be affected by host tumor suppressor, innate immune, and inflammasome responses. 30 Resistance to chronic inflammation has been demonstrated to be a critical element of clonal selection and survival advantage in CHIP. 36 Thereby, these data lend further support to the hypothesis that the residual inflammation latent even in treated PWH may contribute to high CHIP prevalence.…”