NATURAL HISTORY OF SIVMAC BK28 & H824 INFECTION IN MACAQUES

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In this project we seek to identify early predictors of disease progression in M. nemestrina through the use of two closely related simian immunodeficiency virus (SIV) challenge strains that differ markedly in their pathogenicity as determined in M. mulatta. The use of these molecular clones affords the unique opportunity to model fast and slow progression to AIDS while using molecularly defined viruses. Both viral and immune characterizations are performed. Four animals were infected with either SIVmacH824 (acutely pathogenic) or BK28 (minimally pathogenic). Animals infected with SIVmacH824 were euthanized at 19 and 58 weeks postinfection (PI) due to AIDS-like symptoms. The two BK28-infected animals were euthanized at 85 weeks PI; they demonstrated CD4 decline but had not yet progressed to AIDS. Enumeration of cytokine-producing cells demonstrated the induction of Th1-type cytokines in response to infection, although there were no significant differences between an imal s infected with different clones. Interestingly, peak numbers of IFN_-producing cells occurred synchronously with peak viral load. The intracellular cytokine staining technique was refined to allow for the analysis of the antigen-specific cytokine response, an advance that will allow for more precise measurement of the immune response to infection. Having developed a reliable method for measuring plasma levels of RANTES, we showed that RANTES expression was induced and maintained in animals infected with the minimal pathogen (BK28) while RANTES levels dropped after induction in the one H824-infected animal that survived 58 weeks. Cross-sectional studies utilizing samples donated by other investigators supported this finding, demonstrating that plasma RANTES levels are suppressed in animals infected with highly pathogenic viruses. Future projects will incorporate information obtained in this study to develop effective therapies for SIV- and HIV-induced disease. FUNDING NIH grant RR00166. Mulvania, T., Coon, E., Kuller, L., Agy, M.B., Morton, W.R., and Mullins, J.I. Natural history of SIV mac BK28 and H824 infection in Macaca nemestrina. J. Med. Primatol. 27:87-93, 1998.