Abstract
HIV persists in diverse tissues, with distinct cellular reservoirs presenting a major barrier to a cure and requiring targeted therapeutic strategies to address this heterogeneity. Here, we develop tissue models of HIV latency using human tonsillar, intestinal and cervicovaginal tissues. These models reveal differential HIV infection across CD4+ T-cell subpopulations, with ART partially restoring CD4+ T cells and reducing intact HIV DNA. T follicular helper cells (TFH CD69+ CCR7-) are the primary inducible reservoir in tonsils, while tissue-resident memory cells (TRM CD69+ CD49a+) dominate in the intestine. Identification of markers for inducible reservoirs shows that CD69, CD45RO, and PD-1 are shared across tissues, while CXCR5 in tonsils and CD49a in the intestine act as tissue-specific markers. Furthermore, using different latency reversal agents (LRAs) demonstrates that Histone Deacetylase Inhibitors (HDACis) fail to induce HIV in any tissue, the SMAC mimetic AZD5582 is effective only in a resident-memory CD4+ T-cell subpopulation in the intestine, and IL-15 exhibits the broadest reactivation potential across tissues and CD4+ T-cell subsets. These models provide insights into the inducible reservoir's composition in different tissues and inform strategies for its elimination.