Pre-Clinical Development of Novel Immunotherapies for HIV-1

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

For more than 30 years, under project AI000855-26, the HIV-Specific Immunity Section has investigated the CD8+ T cell response to HIV-1 using the cells of rare patients that naturally control HIV-1, long term nonprogressors or elite controllers (LTNP/EC), in comparison with most patients that fail to control the virus. By far the most robust correlate of immunologic control of HIV-1 is the ability of CD8+ T cells to kill autologous HIV-1-infected CD4+ T cells (Migueles et al., Immunity, 2008). Researchers are engaged in very large efforts to develop therapeutic vaccines and immunotherapies for HIV-1. However, there is no knowledge of what the defect is in CD8+ T cell mediated killing that would guide targeted immunotherapy. Over the past 14 years we have used transcriptomics and proteomics to understand the defect in CD8+ T cell mediated killing in progressors at the subcellular level. Candidate proteins that are differentially expressed based upon transcriptomic or proteomic data are first confirmed by flow cytometry. Candidate proteins have been identified and mice were immunized with viral vectors expressing the gene of interest. Monoclonal antibodies have been isolated and confirmed for binding their target antigen and blockade of function. They are then being confirmed to be associated with the targeted function in assays of proliferation, perforin expression, and cytolytic killing. The best monoclonal antibodies will then undergo in vitro affinity maturation. The cause-and-effect relationship of gene product targets is being further established by interruption of function using monoclonal antibodies or CRISPR/Cas9 editing. Those candidates that are clearly causally related to CD8+ T cell dysfunction may then be further tested in the appropriate animal models and ultimately clinical trials.