Characterization of Allogeneic T Cells Mediating HIV Cure

PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (ART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Five individuals, Timothy Brown (Berlin Patient), Adam Castillejo (London patient), Paul Edmonds (City of Hope patient), Marc Franke (Düsseldorf patient), and the New York City patient who has not released their identity were cured of HIV following leukemia-related, MHC- matched, allogeneic hematopoietic stem cell transplantation (alloSCT). How alloSCT mediates cure of HIV is unknown. Using our alloSCT model in Mauritian cynomolgus macaque (MCM), we have demonstrated that the allogeneic immune response can potently purge the latent reservoir. Therefore, we hypothesize that allogeneic T cell responses targeting minor antigens mediate HIV cure similar to how they mediate cure of leukemia. We propose here to define the allogeneic T cell responses in both the individuals who were cured of HIV, as well as the two MCM cured of SIV following alloSCT. In specific aim 1, we will define the allogeneic T cell responses and their targets in three of the individuals cured of HIV (Adam, Paul, and Marc), as well in a number of other cases where individuals underwent alloSCT and experienced a disappearance of HIV from the blood. In specific aim 2, we will define the allogeneic T cell responses and their targets in the two MCM cured of SIV post alloSCT, as well as in a further longitudinal cohort of SIV+ MCM that underwent alloSCT and experienced a decrease in the viral reservoir. In aim 3, we will adoptively transfer T cells expressing human or MCM allogeneic T cell receptors into HIV+ humanized mice or SIV+ MCM, respectively, to measure the safety and efficacy of allogeneic T cells for HIV cure. This work would expand our knowledge of the mechanism of HIV cure in the setting of allogeneic HSCT and establish a new therapeutic approach for HIV cure.