Novel cell and gene therapy for HIV cure - Modified Project Summary/Abstract Section This application represents a well-integrated multi-project research program to improve and implement an emerging gene and cell therapy technology for HIV cure. Previous work demonstrated that a rhesus CMV based SIV vaccine protected 50% of macaques from persistent SIV infection with the correlate of protection being CD8+ T cells that recognized SIV peptides in the context of MAMU-E1-4. The laboratory of Dr. Goepfert demonstrated the presence of HLA-E-restricted HIV-specific immune responses. Preliminary data generated by Drs. Garcia and Wahl recently established in vivo proof-of-principle in BLT humanized mice that HLA-E-HIV-peptide TCR transduced CD8+ T cells can reduce the HIV reservoir as measured by a 50% reduction in intact proviral DNA. Additional in vitro preliminary data demonstrated that the efficacy of HLA-E-HIV-peptide TCR transduced CD8+ T cells can be enhanced by anti-HLA-E-VL9 antibodies generated by Drs. Haynes and Azoitei by preventing inhibitory interactions with the CD94/NKG2A receptor on T cells. The overall goal of this program is to demonstrate that HLA-E-peptide complexes on HIV-infected cells can be targets for antibodies, NK cells or CD8+ T cells leading to their destruction and thus, clearance of HIV infection. Our application represents a logical extension of an ongoing collaboration between a well-established group of outstanding investigators, Dr. Goepfert (Project 1), Drs. Azoitei and Haynes (Project 2) and Drs. Garcia and Wahl (Project 3). Our overall hypothesis is that cell and gene-based therapy approaches targeting the minimally polymorphic HLA-E molecules will provide a strong in vivo therapeutic effect, reducing the HIV proviral DNA load in HIV-infected myeloid and T cells. Our overall specific aims are to 1) produce novel and improved HLA-E-HIV peptide specific TCRs and CARs and evaluate their in vitro specificity and antiviral function when transduced into human T cells as cell and gene based therapy, 2) determine if HLA-E-HIV-peptide TCR transduced CD8+ T cells can target HIV-infected myeloid and CD4+ T cells in vivo in HIV-infected humanized mice, thus reducing viral loads and the HIV reservoir, and 3) determine if anti-HLA-E-peptide specific antibodies can enhance or mediate HIV suppression in vivo in HIV-infected humanized mice. Our two private sector partners T-Cypher and Accelevir will use their expertise and resources to carry out the proposed work and to assist with progressing products derived from this research for eventual FDA licensure and commercialization. The proposal also includes an Administrative Core led by Dr. Garcia that will provide management, coordination and supervision of scientific and fiscal aspects of the program. Our proposal includes a milestone plan with clear timelines and plans for an INTERACT meeting with the FDA. Accomplishment of the overall goal and specific aims of this proposal will provide the HIV cure field with a powerful new armamentarium for reducing the latent pool of HIV-infected myeloid and T cells.
