SBIR-STTR Award

The Human immunodeficiency virus (HIV) is the etiological agent of AIDS. To date, there are only two FDA approved drugs which provide direct antiviral activity against this virus, and the toxicities and emerging resistance limit their widespread utility. In order for new and efficacious anti-HIV agent to enter human clinical trials, small animal models are required to demonstrate in vivo activity. Since HIV is a uniquely human virus, novel means are required to introduce this virus into rodent hosts. One such means is through the xenotransplantation of human HIV permissive cells into sublethally irradiated athymic mice. We have previously demonstrated that the CEM cell line infected with the III-B strain of the HIV can reproducibly demonstrate high levels of p24 antigenemia using this novel approach. With anticipation of expanding this model into a fully accepted and valid small animal model of HIV infection for efficacy evaluation of pharmaceutical compounds, it is the overall objective to continue to refine this model. This will be accomplished by expanding the transplantation aspect to include HIV permissive cells of various phenotypes, by expanding the HIV strains (including AZT resistant & primary) capable of replication within this system, and by introducing other well established means of measuring viral infectivity (i. e., FACS analysis). This additional information will provide a firm basis to design the experiments required for drug therapy determinations in this animal model system.Awardee's statement of the potential commercial applications of the research: Most pharmaceutical companies currently have drugs which are being investigated for anti-HIV activity. With public pressure for the FDA to approve these drugs more rapidly, these companies are faced with placing these drugs into clinical trials early, and/or using monkey trials. Our proprietary animal model has the potential to accelerate drug development, and reduce costs for these clients of ViroMED.National Institute of Allergy and Infectious Diseases (NIAID)

The Human immunodeficiency virus (HIV) is the etiological agent of AIDS. To date there are only three FDA approved drugs which provide direct antiviral activity against this virus, and both toxicities and emerging resistance limit their widespread utility. In order for new and efficacious anti-HIV agents to enter human clinical trials, small animal models are required to demonstrate in vivo activity. Since HIV is a uniquely human virus, novel means are required to introduce this virus into rodent hosts. One such means is through the xenotransplantation of human HIV permissive cells into sublethally irradiated athymic mice. It is the overall objective of this proposal to fully validate the "Irradiated, Nude Mouse, HIV/Humcan Cell Xenotransplant System" for the preclinical efficacy evaluation of potential therapeutic drugs for the treatment of HIV infection.In order to meet this objective, the following specific aims will be pursued:1) expanding the quantitative viral replication parameters used and the number of data points gathered to indirect immunofluorescent assays, reverse transcriptase activity, revocery and titration of infection virus from plasma and infected cells, and quantitative viral RNA and DNA assays;2) extensive testing of AZT as the standard of efficacy (e.g., dose ranging, delayed or short term therapeutic administration);3) testing of other established antiretrovirals and promising compounds previously shown effective against HIV in vitro or in other model systems; and4) multiple agent testing for additive and/or synergistic effects.The results will show that the xenotransplantation of HIV-infected cells into nude mice can provide a cost-effective, predictive model in which to test putative anti-HIV compounds.National Institute of Allergy and Infectious Diseases (NIAID)