In this project we seek to identify early predictors of disease progression in M. nemestrina through the use of two closely related 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 being performed. Four animals were infected with either SIVmacH824 or BK28. Viral load measurements were taken at least monthly and H824, determined to be the more pathogenic virus in rhesus macaques, produced a viral load that was consistently 1-2 logs higher than the viral load produced by BK28 through week 20. One animal infected with H824 was euthanized at 19 weeks postinfection. The viral loads in the three remaining animals, regardless of inoculum, declined to undetectable levels. Despite this decline in viral load, the remaining H824-infected animal progressed to AIDS at 40 weeks postinfection and was euthanized at 58 weeks due to AIDS-like symptoms. The two BK28-infected animals continue to thrive although they do demonstrate CD4 decline. Enumeration of cytokine-producing cells was performed through week 16; the results demonstrated the induction of IFN(-positive CD4+ and CD8+ cells, although there were no significant differences between animals infected with different clones. Interestingly, peak numbers of IFN(-producing cells occurred synchronously with peak viral load. We are continuing these assays throughout the course of infection and are incorporating additional cytokine and activation markers to better examine the cytokine response. We examined plasma levels of RANTES and found that expression was maintained in BK28-infected animals despite decline of viral load. RANTES levels dropped subsequent to the drop in viral load in the one H824-infected animal that survived 58 weeks. These results strongly support the hypothesis that there would be a differential pathogenesis in M. nemestrina. Future projects will incorporate information obtained in this study to develop effective therapies for SIV- and HIV-induced disease.