Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4+ T cell reservoir
Vincent H. Wu, Jayme M.L. Nordin, Son Nguyen, Jaimy Joy, Felicity Mampe, Perla M. Del Río Estrada, Fernanda Torres-Ruiz, Mauricio González-Navarro, Yara Andrea Luna-Villalobos, Santiago Ávila‐Ríos, Gustavo Reyes‐Terán, Pablo Tebas, Luis J. Montaner, Katharine J. Bar, Laura A. Vella, Michael R. Betts
Abstract
Abstract Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4 + T cell reservoir from ART-treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by new and known surface markers within total and individual memory CD4 + T cell subsets. We further uncovered new epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.