Generating Robust anti-HIV CD8 T cells using HIV-targeted Liposomal Vaccines

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Generating Robust anti-HIV CD8 T cells using HIV-targeted Liposomal Vaccines Project Summary: HIV remains a major public health issue in the US, with thousands of new infections every year. While advancements in anti-retroviral therapies (ART) have increased patient lifespans, ART does not cure HIV infection, leaving patients reliant upon ARTs. HIV vaccines have had little success, owing to the immune evasion, high mutability, and latent viral depots of HIV. Here, we propose a new strategy for therapeutic HIV vaccines, the Nanotrap Therapeutic Vaccine (NTV). NTVs are modified liposomes consisting of HIV targeting molecules that bind gp120 and/or gp41 and adjuvants that skew innate immune responses toward Th1 and CD8+ T cell responses. NTVs are designed to be injected after HIV infection, but concurrent with ART therapy when circulating viral loads are high. NTV will bind circulating HIV and be phagocytosed by local APCs, thereby co-delivering both HIV viral particle and adjuvant to APCs, activating them. The activated HIV+ innate immune cell will traffic to the lymph node and stimulate HIV specific CD8+ T cells, which can eradicate latent viruses. This proposal has two aims. First, we will optimize the HIV binding moiety of NTVs. By selecting from a library of known gp120 and gp41 targeting molecules, typically used to inhibit HIV viral entry, we can synthesize lipid formulations, incorporate them into liposomes, optimize their formulation and verify that these bind HIV and inactivate the virus from infecting other cells. Second, after screening potential Th1 skewing adjuvants, we will formulate adjuvant loaded NTVs and verify that these are taken up by local innate immune cells and can generate anti-HIV CD8+ T cell responses both in vitro and in vivo. This project is innovative because 1) NTVs selectively generate effector T cell responses, which have been shown to eliminate latent viral depots and 2) NTVs can generate immune responses specific to the circulating virus in each patient, overcoming HIV’s high mutability evasion strategy. If successful, this proposal would generate a new class of HIV vaccine and potentially be the first step to curing HIV.