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

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.