Background
Tissue resident memory T cells (TRMs) protect the gut mucosal barrier against microbial invasion by exerting rapid and localized effector functions while restraining excessive inflammation. Yet, pathogens can evade immune clearance and persist. The gut is a major HIV-1 reservoir in people living with HIV-1 (PLWH). However, given the rarity of HIV-1-infected cells (<0.1%) and the lack of selection markers, how HIV-1-infected cells survive and evade immune clearance in the gut remain unknown.
Methods
To determine mechanisms of HIV-1 persistence in the gut, we coupled single-cell DOGMA-seq and TREK-seq to simultaneously capture chromatin accessibility, transcriptome, 156 surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in the same cells from colon biopsy samples of ten PLWH under antiretroviral therapy (ART) and five uninfected donors.
Results
We identified 49,205 CD4+ T cells, including 99 HIV-1-infected cells, and 51,539 CD8+ T cells in the gut. Gene regulatory network analysis and multiomic profiling revealed BACH2 as the leading transcription factor that shaped gut T cell programs. While IRF drove effector T cell responses and clonal proliferation, BACH2 restrained effector programs and increased cytokine receptor expression to maintain long-term survival of tissue resident memory T cells (TRMs). TRMs accounted for half (55.1%) of gut CD4+ T cells, but the majority (80.81%) of HIV-1-infected CD4+ T cells were TRMs. HIV-1-infected cells had increased BACH2 and RORC transcription factor activity, TRM (CD49a, CD69, CD103) surface protein expression, Th17 (CCR6), and long-lived memory (IL7R) gene expression (q < 0.05, Wilcoxon rank-sum test). In vitro validation revealed HIV-1 preferential infection and persistence in CCR6+CD4+ TRMs (q < 0.05, Wilcoxon rank-sum test).
Conclusions
Overall, BACH2-driven TRM program restrained effector T cell functions and maintained long-lived TRMs. The long-lived nature of CD4+ TRMs allowed HIV-1-infected cells to upregulate survival cytokine receptors, escape activation-induced cell death, and persist in the gut. Our work identified BACH2-driven TRM program as a new therapeutic target for HIV-1 eradication strategies.
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