INFECTIVITY OF HSIV-VIF CHIMERA IN PIGTAILED MACAQUES

University Of Washington, Seattle WA

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Abstract

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. Our lab showed that pig-tailed macaques are unable to express functional isoforms of TRIM5-alpha, which has been identified as a host factor that restricts the replication of HIV-1 in rhesus monkeys. Therefore, it is possible that HIV-1 will only need to overcome restriction by another host factor, APOBEC3G/F, 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 also seroconverted by wk 4. However, plasma viral load fluctuated between 102-103 copies/ml between 3-10 months after infection and remained at baseline (d102 copies/ml) thereafter (now at 14 months post-inoculation). These results indicate that as yet unidentified factors, in addition to APOBEC3G/F and TRIM5-alpha may contribute to the control of HSIV-vif infection in vivo. Current work is focused on the identification of these unidentified host factors and further improvements on the design of HSIV-vif chimera to allow sustained replication in vivo.