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. Loss of CD4 T lymphocytes is the central pathological effect in HIV, SHIV and SIV infections in humans and macaques. Both infected and non-infected T cells are affected by this loss. Primate models are excellent for examining loss of infected cells but, they are adapted for examining loss of non-infected bystanders. We used CAEV, a natural lentivirus of goats, that does not infect T-cells to produce chimeric viruses expressing HIV/SIV accessory genes involved in the killing of CD4 T cells. We examined the killing properties of these viruses in cell culture systems in which T lymphocytes are exposed to productively infected macrophages expressing the HIV/SIV accessory proteins. We have shown that CAEV-nef and CAEV-VpxVpr induce apoptotic death on bystander T cells. We generated a new chimeric virus expressing simultaneously Nef, Vpr and Vpx that we wanted to use to infect 3 month old and new born goats and to evaluate the cell death of bystander T lymphocytes. A second chimeric virus containing all genes of SHIVKU2 under the transcriptional control of CAEV LTRs was produced. These LTRs have constitutive promoter that is Tat-independent. This virus replicated productively in CEM cells and killed the great majority of these cells in culture while the parental caused minimal effect. When tested for co-receptor usage this virus was found to be highly associated with the CCR5 in contrast to the parental that uses the CXCR4. The properties of this virus in infected monkeys are being examined currently. Replacement of envelope gene of SHIVKU2 with that of CAEV did not generate an infectious virus yet.
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