This project is aimed at evaluating the efficacy of a novel non-nucleosidic reverse transcriptase (NNRT)-inhibitor at i) lowering viral loads in disseminated infection and ii) preventing the establishment of infection by early treatment onset post infection in collaboration with the Tsukuba Primate Center in Japan and Bayer AG (Yahukin, Japan). Since this drug is specific for HIV-1 RT and does not inhibit SIV-RT, a chimeric virus was developed where the HIV-1 Hxb2 RT gene replaced the SIVmac239 RT gene. Preliminary data established the infectious potential of the isolate and the efficacy of the NNRT inhibitor (IC90) alone or in combination in vitro. Toxicity studies were also performed by testing the effect of the compound on various cell-mediated immune functions in vitro. A total of 4 pharmakokinetics studies were performed in macaque monkeys in Japan to determine mode of administration and bioavailability of the drug in vivo. Phase 1 of the animal experiment conducted at Yerkes was aimed at characterizing the animal infectious doses of the SHIV-RT stock, the kinetics of viral loads and virulence of the SHIV-RT isolate in vivo. Three groups of 2 macaques each were administered 100, 10 or 1 TCID50 of the SHIV-RT I.V. and the animals were monitored for plasma and cellular viral loads, phenotypic profiles and clinical symptoms. All animals became infected and after resolution of the acute infection, treatment with the NNRT inhibitor was initiated for a total of 4 weeks to evaluate the induced decrease in viral loads in animals previously infected. Marked decreases in viral loads were noted in all treated animals, yet the 3 monkeys that had high viral loads (<106/ml) prior to treatment showed rapid emergence of drug resistant virus isolates 3 weeks after treatment inception, suggesting that monotherapy with this type of antiviral compound will be of limited value. FUNDING Tsukuba Primate Center $119,010 1/01/98 - 12/31/98 Tsukuba Japan Bayer AG Yakuhin, Yakuhin, Japan PUBLICATIONS None P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center
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