Endogenous Retroelement Expression in the Gut Microenvironment of People Living with HIV-1

Abstract

SummaryBackgroundEndogenous retroelements (EREs), including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), comprise almost half of the human genome. HIV-1 infects a target cell already possessing ancient retroviral genetic material, and exogenous HIV-1 infection modulates the expression of cell associated EREs. Following initial HIV-1 infection, there is a rapid destruction of CD4+ cells in the gut associated lymphoid tissue (GALT). Our previous studies of the interferome in the gut suggest potential mechanisms regarding how IFNb may drive HIV-1 gut pathogenesis. As ERE activity is suggested to partake in type 1 immune responses and is incredibly sensitive to viral infections, we sought to elucidate underlying interactions between ERE expression and GALT dynamics in PLWH.MethodsERE expression profiles from bulk RNA sequencing of colon biopsies and PBMC were compared between a cohort of PLWH prior to or within 7 days of initiating antiretroviral therapy (ART) (n=19) and uninfected controls (n=13). Individual EREs were then compared with the profiling of uninfected gut CD4+ T cells activated with type 1 interferons (IFN-Is) (n=3) to elucidate potential mechanisms for their induction in PLWH.Findings59 EREs were differentially expressed in the colon of PLWH when compared to uninfected controls (Wald’s Test with Benjamin-Hochberg correction: padj < 0.05 and FC ≤ −1 or ≥ 1). Of these 59, 12 EREs were downregulated in PLWH and 47 were upregulated. Colonic expression of the ERE loci LTR19_12p13.31 and L1FLnI_1q23.1s showed significant correlations with CD8+ T Cells and dendritic cell subset frequencies in the GI tract (Spearman’s Correlation: p value < 0.05). Furthermore L1FLnI_1q23.1s showed a significant upregulation in the blood of PLWH when compared to uninfected controls (T test: p <0.05) suggesting a common mechanism of differential ERE expression in PBMC and GALT.InterpretationERE activity has been largely understudied in genomic characterizations of human pathologies. We show that the activity of certain EREs in the GI tract of PLWH is deregulated, supporting our hypotheses that their underlying activity could function as (bio)markers and potential mediators of pathogenesis in HIV-1 reservoirs.FundingNCI CA260691 (DFN) and NIAID UM1AI164559 (DFN).