SIV & HIV 1 RECOMBINANTS SHIVSUBTYPE E ENV

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Significance Recombinant SHIVenv clones are a means to analyze the role of HIV-1 env genes in vivo for viral transmission across mucosal membranes and for SAIDS pathogenesis. Additionally, vaccines based on HIV-1 immunogens can be tested for efficacy by challenge with such recombinant clones. Objectives An animal model to study both HIV-1 infection and AIDS pathogenesis is not available. To analyze function of specific HIV-1 genes in vivo, SIV/HIV-1 recombinant viruses (designated SHIV) have been constructed by replacing genes in the pathogenic clone SIVmac239 with counterpart HIV-1 genes. We have made SHIV clones containing the envelope (env) gene of various HIV-1 subtype-E isolates for analysis in vivo in rhesus macaques. Results SHIV-Thai-E, containing the env gene of the HIV-1-9466 isolate from Thailand, re-plicates in human and baboon lymphocytes but not in macaque lymphocytes. Analysis by PCR revealed that this species restriction is at a step early in viral replication, prior to initiation of viral DNA synthesis. However, SHIV-CAR-E, containing the env gene of the HIV-1-CAR402 isolate from Africa, replicated efficiently in both human and macaque lymphocytes. Juvenile macaques were infected with SHIV-CAR-E by the intravenous and intravaginal (mucosal) route with cell-free virus. These animals exhibited moderate virus loads and produced anti-viral antibodies; no hematologic abnormalities or other disease signs were noted for an observation period of 6 months. Future Directions The step in viral replication that restricts SHIV-Thai-E in macaque cells is being analyzed by biochemical methods; this focus is on virion attachment, co-receptor usage, and fusion entry. A rapid serial passage of SHIV-CAR-E will be performed in juvenile macaques to obtain a pathogenic chimeric virus. KEY WORDS HIV-1 genes, AIDS pathogenesis, SHIV clones FUNDING NIH Grant AI41907