CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness
Simona Mutascio, Talia M. Mota, Lavinia Franchitti, Ashish Sharma, Abigail Willemse, Sydney N. Bergstresser, Hong Wang, Maura Statzu, Gregory K. Tharp, Jared Weiler, Rafick‐Pierre Sékaly, Steven E. Bosinger, Mirko Paiardini, Guido Silvestri, R. Brad Jones, Deanna A. Kulpa
Abstract
HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8 + T cells from people with HIV may suppress HIV expression via non-cytolytic mechanisms, but the mechanisms responsible for this effect remain unclear. Here, we used a primary cell-based in vitro latency model and demonstrated that co-culture of autologous activated CD8 + T cells with HIV-infected memory CD4 + T cells promoted specific changes in metabolic and/or signaling pathways resulting in increased CD4 + T cell survival, quiescence, and stemness. Collectively, these pathways negatively regulated HIV expression and ultimately promoted the establishment of latency. As shown previously, we observed that macrophages, but not B cells, promoted latency in CD4 + T cells. The identification of CD8-specific mechanisms of pro-latency activity may favor the development of approaches to eliminate the viral reservoir in people with HIV.