Postinoculation PMPA treatment, but not preinoculation immunomodulatory therapy, protects against development of acute disease induced by the unique simian immunodeficiency virus SIVsmmPBj

The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shoc k, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of v irus biology suggest that immune activation contributes to pathogenesis. Th ese biological characteristics include induction of peripheral blood mononu clear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the r ole of immune activation and viral replication on disease induction, animal s infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a p otent immunosuppressive agent, or PMPA, a potent antiretroviral agent. Whil e PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal d isease. However, these animals did show some evidence of modulation of immu ne activation, including reduced levels of CD25 antigen and FasL expression , as well as lower tissue viral loads. In contrast, macaques treated postin oculation with PMPA were completely protected from the development of acute ly lethal disease. Treatment with PMPA beginning as late as 5 days postinfe ction was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated c ontrols, Although PMPA-treated animals showed acute lymphopenia due to SIVs mmPBj14 infection, cell subset levels subsequently recovered and returned t o normal. Based upon subsequent CD4(+) cell counts, the results suggest tha t very early treatment following retroviral infection can have a significan t effect on modifying the subsequent course of disease. These results also suggest: that viral replication is an important factor involved in PBJ-indu ced disease. These studies reinforce the idea that the SNsmmPBj model syste m is useful for therapy and vaccine testing.