With 34 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine that protects against heterosexual transmission remains a top global health priority. We have recently discovered the existence of a novel class of CD8+ T cells recognizing peptide antigen presented by the non-classical molecule MHC-E. In contrast to the staggering diversity of classical HLA-A, -B, and -C alleles present in the human population, only two HLA-E alleles exist, which differ only by one amino acid and are functionally identical. Furthermore, while classical HLA-A and -B molecules are removed from the surface of HIV-infected cells by the Nef protein, HLA-E surface expression increases dramatically. These desirable traits raise the possibility that a vaccine targeting HLA-E could induce a universal T cell response, which would be unaffected by the immune evasion activities of the Nef protein, and shared by all vaccinated individuals. To investigate this intriguing idea, we will define MHC-E restricted CD8+ T cell epitopes in both humans and rhesus macaques in specific aim 1 of this proposal.
In specific aim 2, we will characterize the functionality, TCR usage, and antiviral efficacy of these unusual T cells.
In specific aim 3, we wil vaccinate macaques with a novel vaccine approach that delivers SIV antigens simultaneously with viral proteins identified to trigger MHC-E presentation. We will subsequently challenge these animals with low-dose SIV to determine the protective capability of MHC-E-restricted CD8+ T cells. Successful completion of these studies could define an entirely new approach to inducing universal protective immunity by mobilizing the monomorphic MHC-E molecule.
The development of a prophylactic HIV vaccine remains one of the top global health priorities, and novel vaccine targets are urgently needed. In contrast to the staggering diversity of classical HLA alleles, only two HLA-E alleles exist in the human population. We propose here to develop a universal CD8+ T cell vaccine for HIV by mobilizing the monomorphic HLA-E allele for anti-HIV immunity via a novel vaccine approach.
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