Identifying the Killing Pathway that Mediates CD4 T-cell Depletion in HIV-Infected Lymphoid Tissues

Award amount: 40,000.00

Zhiyuan Yang, PhD, Recipient

Progressive depletion of CD4 T cells is a hallmark of untreated acquired immune deficiency syndrome (AIDS), but the mechanism of CD4 T-cell death by HIV remains poorly understood. While HIV directly infects and kills CD4 T cells, the number of productively infected cells in vivo cannot account for the massive CD4 T-cell losses that occur. To better understand how HIV infection depletes CD4 T cells, we used primary human lymphoid aggregate cultures (HLAC) from human tonsil and spleen tissue. Using this system three surprising discoveries emerged. 1) Quiescent 'bystander' CD4 T cells, which are not permissive to productive X4-HIV infection, die in huge numbers, but their death involves abortive infection and accumulations of incomplete cytosolic HIV DNA. 2) Rather than dying due to a toxic action of products encoded by HIV, these CD4 T cells die as a result of a powerful host innate immune defense program launched against the virus. This program involves production of interferon-?, and activation of caspase-3 and caspase-1 3) Ultimately, this response leads to inflammasome assembly and caspase-1 activation that promotes release of bioactive IL-1? and pyroptosis, an intensely inflammatory form of programmed cell death. These findings raise several key questions. How the cytosolic DNA is sensed? What inflammasome is activated in these dying cells? I propose to apply biochemical and molecular approaches to isolate the cytoplasmic sensor(s) that recognize HIV DNA reverse transcripts, and the inflammasome that activates caspase-1 in response to such DNA intermediates. Together, these studies promise to provide exciting new perspectives on HIVinduced cell death, and potentially open the door to use for an entirely new calls of 'anti AIDS' drugs agents that would curb CD4 T-cell loss and suppress the inflammatory response that is pivotal in HIV pathogenesis.