My lab has provided CTL assays after infections, vaccinations, and treatments in the rhesus/AIDS model. We discovered that uninfected animals often have lytic activity to cells expressing SIV envelope protein and that this lytic activity is not MHC-restricted. We screened 56 uninfected monkeys and found half of them had high lytic activity and half had low MHC-unrestricted lytic activity to SIV env. We predicted that SIV infection would be cleared rapidly in animals with high env-specific lytic activity and slowly in animals with low lytic activity. Accordingly, we infected 11 animals and found the opposite of our prediction to hold true, those with high lytic activity died more rapidly than those with low lytic activity (J. Virol. 1999, in press). This indicated that high lytic activity does not simply destroy virus-infected cells, but has a more devastating effect on the organism. We characterized the lytic activity to be mediated by FasL and its receptor Fas, which was activated by the expression of env in target cells. Lysis could be blocked with antibody to FasL. A collaboration with H. Yagita contributed monoclonal antibody to FasL which we injected into 4 animals to therapeutically delay disease progression. The animals were pre-selected to have high lytic activity (high FasL) and therefore to have rapid disease progression. The 4 animals are in their 4th month of study and so far, have slow disease progression as predicted. After making additional measurements of surrogate markers of disease progression, we will be ready to publish these remarkable findings. KEY WORDS SIV, cytolytic activity, AIDS progression. FUNDING NIH RO1 AI32107-02, NIH RROO167; DARPA PUBLICATIONS Dykhuizen M., Mitchen J.L., Montefiori D.C., Thomson J., Acker L., Lardy H., Pauza CD. 1998. Determinants of disease in the simian immunodeficiency virus-infected rhesus macaque characterizing animals with low antibody responses and rapid progression. J. Gen. Virol. 79 2461-2467. Note This abstract also represents a colloborative subproject.
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