IMMUNOLOGICAL AND VIROLOGICAL STUDIES OF NATURAL SIV INFECTION OF DISEASE-RESISTANT NONHUMAN-PRIMATES

Nonhuman primates naturally infected with simian immunodeficiency viru s (SIV), while maintaining chronic viremia, do not develop any disease associated with lentiviral infection. Thus they provide a unique mode l to define the mechanism(s) by which they remain infected but disease -resistant. The purpose of this article is to summarize our current kn owledge of the virological and immunological studies that have been pe rformed in sooty mangabeys naturally infected with SIVsmm and in disea se-susceptible rhesus macaques experimentally infected with SIVsmm. Da ta on virological studies demonstrate that the naturally infected soot y mangabeys are infected predominantly with SIV that have nef sequence s distinct from those shown to cause disease in the inappropriate host , a factor which may contribute to disease resistance, Hyperimmunizati on with a variety of antigens or chronic infection contributes to acce lerated disease and death in rhesus macaques if hyperimmunizations are initiated at the time of SIV infection, whereas similar hyperimmuniza tion and chronic infection do not lead to disease in naturally infecte d seropositive sooty mangabeys. However, in both species infected with SIV, hyperimmunization leads to increased virus load, suggesting that virus load per se cannot account for disease, at least in naturally i nfected nonhuman primates. Immunological studies concerning changes in subsets of T cells, based on cytokine profile (TH0/TH1/TH2), showed t hat whereas rhesus macaques early post SIV infection show a dominant T H1 profile, this profile rapidly changes to TH0. On the other hand, ma ngabeys continuously demonstrate a TH2-like profile. Studies also show ed a high frequency of in vivo-activated cells in the peripheral blood of SIV-infected rhesus macaques and mangabeys. Of interest, however, is the finding of a similar level of in vivo-activated cells from ELIS A seronegative mangabeys. Although cells from SIV-infected mangabeys f ail to show increased levels of apoptotic cells following incubation w ith immobilized anti-CD3, PBMC from rhesus macaques at varying time in tervals do show increased levels of apoptotic cells, an increase which is predominantly seen in CD8(+) T cells and is unrelated to levels of viremia. Sooty mangabeys maintain a high frequency of CD8(+) T cells that regulate virus replication throughout their lifetime, a frequency that develops prior to ELISA-based seroconversion, whereas rhesus mac aques only show a frequency of CD8(+) T cells high enough to regulate virus replication shortly post infection, and this regulatory function is gradually lost prior to CD8(+) cell loss and death, HIV and SIV in fection do have profound effects on the expression of a number of cost imulatory and adhesion molecules, There appear to be differences in th e nature of the intracellular phosphorylated proteins in cells from ac tivated rhesus macaques and mangabeys. We believe that careful studies of the detailed mechanisms of the issues described above may provide an understanding of the constellation of virological and immunological mechanisms responsible for the disease-resistant state of naturally i nfected sooty mangabeys. These findings can be employed for evaluating a nonvirus sterilizing form of SIV/HIV vaccines.