Duan, L.; Sanders, M. A.; Wietgrefe, S. W.; Tian, D.; Southern, P. J.; Anderson, J.; Wieking, G.; Schacker, T. W.; Haase, A. T.

Activated CD4+ T cells have long been considered the principal source of HIV production before treatment and reactivated latently infected cells the source of virus rebound on treatment interruption, based largely on studies of peripheral blood T cells. Here we show before ART in the lymphoid tissue reservoir that HIV-producing resting CD4+ T cells are essentially the sole source of virus production in germinal centers. Virus is produced in infection complexes of virus bearing follicular dendritic cells (FDCs) that induce high multiplicity multi-HIV-DNA copy infections in overlying resting T cells. HIV production is associated with destruction by PANoptosis (pyroptosis, necroptosis and apoptosis) of interacting antibody-producing populations of FDCs, T cells and B cells. PANoptosis is mediated by the PANoptosome, visualized and defined here as a cellular structure incorporating cytoplasmic and nuclear contents and programmed cell death pathway components in a nodal latticework that executes cell emptying and disruption. During ART, HIV-producing resting T cells persist in lymphoid tissues when virus is undetectable in peripheral blood. These HIV-producing resting T cells that persist during ART represent an immediate source of virus to reignite infection on treatment interruption and are thus identified as an important new target for functional cure strategies.