Project Grant R01AI181579

HARNESSING THE PATHOGENESIS OF CMV AGAINST HIV - PROJECT SUMMARY/ABSTRACT CD8+ CYTOTOXIC T LYMPHOCYTES (CTLS) PLAY A KEY ROLE PROTECTIVE ROLE IN HIV-1 INFECTION, BUT CANNOT FULLY SUPPRESS THE VIRUS BECAUSE THEY REQUIRE ANTIGEN FOR MAINTENANCE. HIV-1-SPECIFIC CTLS MEDIATE THE SUPPRESSION OF HIV-1 FOR THE "ASYMPTOMATIC" PHASE OF CHRONIC INFECTION. THE CTL RESPONSE PARTIALLY CONTROLS INFECTION, BUT ONCE THE ANTIGEN IS CLEARED TO VERY LOW LEVELS, THEY DECAY TO LOW FREQUENCY RESTING CENTRAL MEMORY CELLS. SINCE CTLS REQUIRE ANTIGEN TO MAINTAIN EFFECTOR FUNCTION, THEY CANNOT FULLY SUPPRESS EVEN IN MOST "ELITE CONTROLLERS," WHO EXHIBIT PATHOGENIC LOW LEVEL INFECTION. TO SUPPRESS HIV-1 FULLY, CTLS NEED TO BE MAINTAINED INDEPENDENTLY OF HIV-1 REPLICATION. CYTOMEGALOVIRUS (CMV) DRIVES CTL PERSISTENCE THROUGH FREQUENT LOW GRADE REACTIVATIONS. FREQUENT SPONTANEOUS NON-PATHOGENIC REACTIVATIONS OF CMV DRIVE PERSISTENT MAINTENANCE OF CMV-SPECIFIC ACTIVE EFFECTOR CTLS. WE HYPOTHESIZE THAT CREATING CTLS RECOGNIZING BOTH CMV AND HIV-1 CAN YIELD SUPERIOR CONTROL OF HIV-1 INFECTION. SUCH CTLS WOULD BE MAINTAINED BY NATURAL CMV REACTIVATIONS TO BE PRIMED AS ACTIVE EFFECTOR CELLS AGAINST HIV-1. TO ACHIEVE THIS GOAL, WE HAVE DEVELOPED A PROTOTYPE BI-SPECIFIC CHIMERIC ANTIGEN RECEPTOR (CAR) THAT RECOGNIZES BOTH CMV AND HIV-1, COUPLING MAINTENANCE TO CMV AND DE-COUPLING MAINTENANCE FROM HIV-1. THIS PROJECT WILL EXPAND THAT EFFORT; SPECIFICALLY WE AIM: 1. TO OPTIMIZE A PANEL OF CMV AND HIV-1 BI-SPECIFIC CARS; 2. TO EVALUATE THE FUNCTION OF THESE CARS IN THE BLT HUMANIZED MOUSE MODEL.