The recent recognition that a host innate antiviral immune response mediates up to 95% of CD4 T-cell (CD4) death during HIV infection has markedly changed our understanding of HIV pathogenesis. Abortively infected resting CD4 are swept up into a fiery, highly inflammatory programmed cell death termed pyroptosis. In sharp contrast to resting lymphoid tissue CD4, circulating blood CD4 are highly resistant to pyroptosis. However, when blood CD4 are co-cultured with lymphoid tissue CD4, CD8, or B cells (likely recapitulating events occurring during blood CD4 trafficking into lymphoid tissues), they become sensitive to pyroptosis. Intimate cell-to-cell interactions are required for sensitization. These findings offer a unique opportunity to use RNA-Seq and Mass-Spectrometry of membrane proteins or PTM-MS to identify the signaling ligand(s) expressed in lymphoid tissue-derived CD4, CD8 and B cells, but not expressed in their closely related blood counterparts. As an alternative approach for identifying the key receptor, blood CD4 will be studied by RNA-Seq and membrane-proteomic before, during and after sensitization with lymphoid cells. Two validation strategies will be pursued. First, candidate genes will be expressed in blood B cells and these cells tested for their ability to sensitize blood CD4 for pyroptosis. In parallel, specific gRNAs/Cas9 will be used to knockout expression of candidates in lymphoid tissue B cells, followed by testing whether these cells have lost capacity to sensitize blood CD4. A similar strategy will be used to identify and validate the receptor(s) present on blood CD4. If successful, these studies could lead to the identification of blocking antibodies or small molecule inhibitors conferring the same resistance to pyroptosis to tissue CD4 that naturally found in blood CD4. These agents could form an attractive ART adjunctive for slowing CD4 depletion and reducing chronic inflammation in the estimated 40-60% of subjects where pyroptosis persists after commencement of ART.