Shared Mechanisms Govern HIV Transcriptional Suppression in Circulating CD103⁺ and Gut CD4⁺ T Cells

Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103⁺ and CD103^- CD4 T cells from the blood and rectum of HIV-negative (HIV^-) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV⁺) individuals. Like gut CD4⁺ T cells, circulating CD103⁺ cells harbored more HIV DNA than did CD103^- cells but transcribed less HIV RNA per provirus. Circulating CD103⁺ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103^- cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103⁺ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, "latent" infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103⁺ CD4⁺ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103⁺ T cells share a cellular transcriptome that more closely resembles that of CD4⁺ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4⁺ or circulating CD103⁺ T cells from circulating CD103^- T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.