SAFETY AND EFFICACY OF SHIV VACCINE IN MACAQUES

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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. Two types of studies were supported in this grant. First, studies were directed to mechanisms regulating neuropathogenesis of SHIVKU infection in macaques. This is an X4 virus that invades the brain during the viremic phase of infection and remains dormant until the animal becomes immunosuppressed as a result of the highly productive replication of the virus in CD4 T lymphocytes. Productive virus replication in the brain was confined to macrophages and neuropathological changes correlated with expression of the chemokine CXCL10 that was toxic to neurons and IL-4 that promoted virus replication in the macrophages. Second, continuation of studies on efficacy of a live vaccine showed that immunity induced by the live vaccine depended on persistence of the vaccine virus, and that following elimination of the virus, the animal became susceptible to fatal disease by pathogenic challenge viruses. The live virus apparently failed to induce memory immune responses. The duration of protection by the live vaccine could be extended by re-immunization with the live vaccine. This re-established the persistent infection and the concomitant protective immunity. The persistent infection was characterized by dormant infection and virus replication could only be reactivated by immunosuppression of the immunized animals with antibodies against CD8 lymphocytes. Following recovery of the CD8 cell count, replication of the vaccine virus was again suppressed