Thursday, November 21, 2024
11/21/2024
Allogeneic cytotoxic ¿d T cells for HIV cure immunotherapy PROJECT SUMMARY HIV Cure strategies based on the “shock and kill” approach require the use of compounds to reactivate HIV from latency and potent immune responses to eliminate HIV-infected cells. Efforts have mostly focused on enhancing HIV-specific CD8 T cell responses but have faced a number of limitations including viral escape, immune exhaustion and inaccessibility to the B cell follicle. ¿d T cells, specially the most abundant peripheral blood population, Vd2 cells, constitute an attractive alternative cytotoxic cell population with unique properties largely exploited in adoptive cell therapies for different malignancies that we have started to explore for HIV cure purposes. In our previous studies, we showed that autologous Vd2 ¿d T cells from people living with HIV (PLWH) ART- suppressed are particularly effective inhibiting HIV replication and the first evidence that expanded Vd2 cells target and eliminate HIV-infected resting CD4 T (rCD4) T cells after latency reversal. These studies constitute the basis for further investigation towards translating this alternative approach into the clinic. Vd2 cells recognize intermediates of the mevalonate pathway in an MHC-unrestricted fashion. They respond to a given challenge by both up and/or downregulating specific receptors depending on the infectious/malignant environment displaying a unique functional plasticity that enables them i) to exert direct cytotoxicity and ii) to initiate and boost adaptive immune responses. Vd2 cell phenotype can be shaped by ex vivo manipulating the mevalonate pathway using Aminobisphosphonates (nBPs) and IL-2 or IL-15 leading to Vd2 cell activation and expansion. Similarly, to NK cells, combination of IL-2 and IL-15 with other cytokines and factors may favor the development of an effector memory phenotype with enhanced cytolytic activity against HIV-infected cells. Additionally, the lack of MHC restriction would allow for an allogeneic adoptive ¿d T cell immunotherapy, that would be required for HIV cure since Vd2 cells are targets of HIV infection. Allogeneic adoptive cell transfer has been explored in the cancer field and merits further investigation for HIV cure. Exploiting these unique features would allow the generation of a cytotoxic effector population with phenotypic and functional properties suited for targeting reactivated HIV- infected cells. Given Vd2 cell functional plasticity, we hypothesize that manipulation of the mevalonate pathway and proper cytokine combinations will allow generation of a universal cytotoxic effector cell product of ex vivo expanded allogeneic Vd2 cells that will recognize and kill HIV-infected cells upon latency reversal. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine whether allogeneic expanded Vd2 cells efficiently target and eliminate HIV-infected cells upon latency reversal and (2) to explore conditions to develop a universal immunotherapy Vd2 effector cell product for HIV cure, and mechanisms of HIV-infected cell recognition.
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