HIV-1 infection stimulates an unusually vigorous cell mediated immune response, including viral-specific cytotoxic T lymphocytes (CTL) which recognize and lyse HIV- infected cells. Because this arm of the immune system is important in the defense against intracellular pathogens, including viruses, and because it fails as individuals progress to AIDS opportunistic infections, we have been interested in bolstering this natural immunity by developing ways to expand selectively HIV-specific CTL lines for infusion into infected patients. Earlier work in our laboratory showed that the CTL from infected patients predominantly recognize a few HIV-encoded peptide epitopes and that the addition of immunodominant peptides can lead to potent T cell lines that can be grown to large numbers and are free of detectable replication-competent virus. We are conducting a pilot clinical trial (DATRI 006) to study the feasibility, toxicity and efficacy of HIV-specific CTL therapy using T cell lines grown with immunodominant peptides. The goal of this project is to build upon this earlier work to improve on the feasibility and effectiveness of viral- specific CTL therapy. To this end, we plan to analyze the stored plasma and PBMC from DATRI 006 patients to help understand whether the infused CTL are likely to persist, what changes occur following treatment in HIV-specific CTL epitopes, viral recognition sequences, state of T cell activation, cytokine secretion profile and frequency of T cell apoptosis. Because our method of growing HIV-specific CTL lines is labor intensive and costly, since it involves extensive characterization of HIV CTL epitopes, which vary from individual to individual, we plan to develop further methods of expanding potent CTL lines that are simpler, but result in lines that are as safe and effective. We also plan to optimize our methods with respect to the concentrations and combinations of cytokines used to propagate the T cells. This work will culminate in the development of the next generation CTL therapy protocol. The execution of this project will heavily depend on the viral sequencing, peptide synthesis and cytokine measurement cores of this cooperative project. In collaboration with Project 2, we plan to investigate whether HIV-specific CTL can be used to aid in the development of therapeutic CD4 T cell lines in advanced patients. The cytokine experiments of Project C will be invaluable in helping to analyze the effects of CTL therapy in DATRI 006 and in developing optimal methods both to expand CTL lines and to treat patients with combination T cell-cytokine therapy. They will also help determine whether antiinflammatory cytokine therapy, which will be developed in Project C, will hae an adverse effect on viral-specific CTL in treated patients.
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