MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4⁺ T cells into CCR5⁺ T_RM -like cells

by Sinmanus Vimonpatranon, Livia R. Goes, Amanda Chan, Isabella Licavoli, Jordan McMurry, Samuel R. Wertz, Anush Arakelyan, Dawei Huang, Andrew Jiang, Cindy Huang, Joyce Zhou, Jason Yolitz, Alexandre Girard, Donald Van Ryk, Danlan Wei, Il Young Hwang, Craig Martens, Kishore Kanakabandi, Kimmo Virtaneva, Stacy Ricklefs, Benjamin P. Darwitz, Marcelo A. Soares, Kovit Pattanapanyasat, Anthony S. Fauci, James Arthos, Claudia Cicala

CD4⁺ tissue resident memory T cells (T_RMs) 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-β, promote the differentiation of CD4⁺ T cells into a distinct subset α₄β₇⁺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_RMs to persistent viral reservoirs and HIV pathogenesis.