Identification of the Inducible HIV reservoir in Tonsillar, Intestinal and Cervical Tissue Models of HIV Latency

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 developed tissue models of HIV latency using human tonsillar, intestinal and cervicovaginal tissues. These models revealed differential HIV infection across CD4 ⁺ T cell subpopulations, with ART partially restoring CD4 ⁺ T cells and reducing intact HIV DNA. T follicular helper cells (T _{FH CD69+ CCR7-} ) were the primary inducible reservoir in tonsils, while tissue-resident memory cells (T _{RM CD69+ CD49a+} ) dominated in the intestine. Identification of markers for inducible reservoirs revealed that CD69, CD45RO, and PD-1 were shared across tissues, while CXCR5 in the tonsils and CD49a in the intestine served as tissue-specific markers. Furthermore, using different latency reversal agents (LRAs) we found that Histone Deacetylase Inhibitors (HDACis) failed to induce HIV in any tissue, the SMAC mimetic AZD5582 was effective only in a resident-memory CD4 ⁺ T cell subpopulation in the intestine, and IL15 exhibited the broadest reactivation potential across tissues and CD4 ⁺ T subsets. These models recapitulate key aspects of HIV infection providing insights into the inducible reservoir’s composition in different tissues and informing strategies for its elimination.