The clinical research component of this application describes an approach for sequential late Phase I and early Phase II studies in a group of 150 to 200 HIV seropositive hemophiliacs. These patients are a subpopulation of 400 multitransfused hemophiliacs who receive comprehensive care at three centers in the mid-Atlantic region and who are well characterized concerning their immune deficiency status. Efficacy of proposed initial therapy with AZT and Acyclovir will be evaluated in a concurrent case control study by measurement of T-cell subsets, serum IFN alpha levels, antigen capture assay, Western Blot analysis, and by neuropsychiatric assessment and clinical outcomes. Inhibition of viral replication will be assessed experimentally by tow unique model systems: (1) an in vitro flow cytometric detection system to identify as few as one HIV infected cell among 10,000 peripheral blood lymphocytes (currently under development by contract with the NHLBI), and (2) an in vivo human tissue xenograft system which we propose to develop and validate in a nude mouse host. To study the immunoreactivity of naturally occurring antibodies, an HIV DNA expression library will be constructed. If clinical status can be correlated with antibody response of infected individuals undergoing therapy, bacterially synthesized proteins will be used to produce monoclonal antibodies against specific HIV epitopes. These antibodies will then be tested for their ability to block HIV infections both in vitro and in vivo. The neutralizing and cytotoxic abilities of naturally occurring antibodies, and their specificities, will be studied using our two experimental model systems. Drug resistance will be assessed in vitro and in vivo in the nude mouse host. It is hoped that these clinical and basic research studies will contribute to a better understanding of the molecular genetics, immonobiology and natural history of HIV infections, and that they will lead to the development of better strategies for early intervention with antiviral drugs or vaccines.
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