This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, there is no animal model for HIV-1 infection and disease because the virus is highly specific for humans. Macaques are generally resistant to HIV-1, with the exception being pig-tailed macaques. A number of reports from WaNPRC in 1990's indicated that certain strains of HIV-1 could infect pig-tailed macaques, although viremia was transient and infection was variable. In the intervening years, there has been significant progress in the understanding of factors that restrict HIV-1 replication in primate species. Two host factors are primarily responsible for restricting HIV-1 infection in rhesus macaques: TRIM5alpha and APOBEC3G/F. These factors interact, respectively, with viral capsid and the Vif proteins. Our lab recently showed that pig-tailed macaques are unable to express functional isoforms of TRIM5 alpha. Although they express a novel form of TRIM, TRIMCyp, it does not restrict HIV-1. Therefore, it is possible that HIV-1 will only need to overcome APOBEC3G/F-mediated restriction to replicate successfully in pig-tailed macaques. To test this hypothesis, we collaborated with Dr. J. Kimata of Baylor College of Medicine, who engineered an HIV-1 clone that includes the vif gene of SIVmne, allowing it to counteract APOBEC3G/F-mediated restriction. This chimeric virus, HSIV-vif, is 96% HIV-1 and 4% SIV. It replicates in stimulated pig-tailed macaque blood cells as efficiently as SIVmne. In this pilot study, we inoculated 2 pig-tailed macaques intravenously with HSIV-vif. Both animals became infected, with plasma viremia detectable 1 wk after infection and reaching a peak between 104-105 copies/ml at wk 2. Both animals seroconverted by wk 4. Although it is too early to tell if infection will sustain, these preliminary data are encouraging and support our notion that studies of diverse macaque species are essential for the understanding of primate lentivirus pathogenesis and the development of relevant animal models for the evaluation of novel therapies and vaccines against HIV/AIDS.
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