Mast cells are one of the least studied yet potentially most important cell lineages involved in persistent HIV- 1 infection for the following reasons: a) mature mast cells are phenotypically and functionally diverse and possess the widest tissue distribution of all hematopoietic cells in extravascular and perivascular spaces in both connective and mucosal tissues; b) they are long-lived, interact closely with T cells and participate in directing T cell-mediated inflammatory processes; c) in addition to their role in IgE-mediated type 1 hypersensitivity, they are also important effectors in other innate immune physiologic and pathophysiologic processes, including responses to tissue injury and infection with bacterial, viral, and helminthic pathogens. Our lab and others have demonstrated that cord blood-derived progenitor mast cells developed in vitro in the presence of IL-6, IL-10 and SCF become transiently susceptible to productive infection with R5-tropic HIV- 1bal and eventually differentiate into mature HIV-1 infection-resistant mast cells. Furthermore, latent infections can be established in mature mast cells and are reversible by stimulation through TLR-mediated signaling pathways. However, it is known that mast cells responding to alternate mitogenic signals in addition to SCF, in particular T cell derived cytokines, evolve into functionally diverse phenotypes. Yet the consequence of such mast cell diversity for their susceptibility to infection with HIV-1 is unknown. In this proposal we present new findings from both in vitro and in vivo studies that suggest that under different cultural conditions progenitor mast cells assume different profiles for susceptibility to HIV-1 or SIV infection than has been previously reported. Our findings suggest that mast cells of different phenotypes may exhibit a wider window of susceptibility to infection during their maturation and may also become infected with X4- as well as R5- tropic strains. Aim one will focus on carefully describing the kinetics and (HIV-1) susceptibility characteristics for progenitor mast cells under T cell-dependent and -independent cultural conditions. Aim two will be devoted to characterizing mast cell-specific factors involved in the establishment of latent HIV-1 infection in different sub-lineages. Aim three will focus on characterizing the consequences of T cell-interactions with HIV-1 infected mast cells in terms of spreading of infection, apoptosis, and cytokine responses.