PATHOGENESIS OF AN X4-TROPIC VARIANT OF SIVMAC239

Tulane University Of Louisiana, New Orleans LA

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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. We have derived, in vitro, a variant of SIVmac239, termed SIVmac239-ST1, that exhibits high efficiency use of X4. We used this new virus to infect four male rhesus macaques to assess the effects of its altered co-receptor usage on in vivo viral replication and host control. In this protocol we intravenously inoculated four Rhesus macaques of Indian origin with 1X103 TCID50 of SIVmac239-ST1. Blood samples were collected for flow cytometry analysis as well as to monitor plasma viral load, humoral immune responses and the overall health of the animals (CBC and Chemistry). CSF was also collected for viral load analysis. Lymph node and intestinal biopsies were used for localization of the virus in situ as well as isolation of leukocytes and flow cytometry analysis. Physical exams were performed to monitor the overall health of the animals. All four animals became infected and had peak viral loads between 6.5 and 7.2 log copies/ml measured by bDNA. The set point of infection ranged between 3.5 and 6.5 log copies/ml. One animal became sick and was humanely euthanized 368 days post-challenge. The other three animals were humanely euthanized on 314 days (n=2) and 371 days (n=1) post-challenge. CCR5 decreased dramatically after infection in all four animals and in the lymph node of one animal. CXCR4 also decreased in the gut of two animals after infection (the other two were not tested). CD4 decreased in the gut of all four animals after infection. CD4 cells steadily declined in the whole blood of the one animal that showed signs of AIDS.