MAdCAM-1 costimulation in the presence of retinoic acid and TGF-beta promotes HIV infection and differentiation of CD4(+) T cells into CCR5(+) T-RM -like cells

CD4(+) tissue resident memory T cells (T(RM)s) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-beta, promote the differentiation of CD4(+) T cells into a distinct subset alpha(4)beta(+)(7)CD69(+)CD103(+) T-RM -like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of T-RM -like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4(+) T(RM)s to persistent viral reservoirs and HIV pathogenesis. Author summary Although antiretroviral drugs strongly suppress viral replication in HIV infected subjects, viral reservoirs persist. To achieve a cure, these reservoirs need to be eliminated. However, the location and identity of persistently infected cells are not well understood. Tissue resident memory CD4(+) T cells (T(RM)s) are a cell type that may play an important role. These cells reside in tissues for extended periods of time and circulate infrequently. To increase our understanding of the role of T(RM)s in HIV reservoirs this study identifies MAdCAM-1 and RA as two key components of the gut immune system involved in the generation of T(RM)s. Treatment of primary CD4(+) T cells with MAdCAM-1 and RA renders cells susceptible to HIV infection and primes them to adopt a T-RM -like phenotype. Addition of a TGF-beta, an anti-proliferative cytokine, induces them to adopt a more complete T-RM -like phenotype. This study provides a new approach toward studying the persistent reservoirs that are a barrier to an HIV cure.