Human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-20 are T- lymphocytopathic lentiviruses that cause AIDS. HIV-1 infections are prevalent in many parts of the world. In vitro studies have shown that the HIV-1 envelope (ENV) gene controls cell tropism, replication kinetics, and cytopathicity. In addition, the env glycoprotein is a target for anti-viral immune responses, and a high degree of sequence variation in env is observed in both interpatient and intrapatient isolates. Currently, animal models to directly investigate HIV-1 infection, functions of viral gene, and pathogenesis are very limited. Several isolates of simian immunodeficiency virus (SIV) as well as some molecular clones of SIV produce a fatal AIDS-like disease in Asian macaques. HYPOTHESIS: The hypothesis is that the role(s) of the HIV-1 env gene in infection can be investigated by constructing recombinant viruses (i.e., chimeras) between SIV and HIV-1 (designated SHIV) and testing these recombinants in rhesus macaques. The env genes of four HIV-1 clones that demonstrate different in vitro properties will be used to replace the env gene of the pathogenic SIVmac239 clone to produce four SHIV chimeras.
SPECIFIC AIM 1 : The objective is to identify an SHIV that persists in experimentally infected juvenile macaques. Viral load, anti- viral immune responses, and clinical signs will be monitored.
SPECIFIC AIM 2; The objective is to analyze cell and tissue distribution of the four SHIVs in macaques. These experiments will determine whether in vitro properties controlled by HIV-1 env correlate with in vivo properties.
SPECIFIC AIM 3 : The objective is to assess sequence changes in the HIV-1 env gene of SHIVs in infected macaques. Viruses will be recovered from various tissues in infected animals, and sequence changes in the env gene(s) will be analyzed.
SPECIFIC AIM 4 : The objective is to augment the potential pathogenicity of SHIV. The SHIV chimeras will be serially passaged in very young macaques. SIGNIFICANCE: A major goal of this project is to establish a non-human primate model to determine the significance of in vitro properties controlled by HIV-1 env gene. In addition, patterns of HIV-1 env gene variation will be analyzed in the animal model. This information may provide insight on mechanisms of selection of viral variant in the host and may also provide a primate system for testing immunogens that elicit protective immune responses against HIV-1.
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