Immunological and virological studies of natural SIV infection of disease-resistant nonhuman primates.

Nonhuman primates naturally infected with simian immunodeficiency virus (SIV), while maintaining chronic viremia, do not develop any disease associated with lentiviral infection. Thus they provide a unique model to define the mechanism(s) by which they remain infected but disease-resistant. The purpose of this article is to summarize our current knowledge of the virological and immunological studies that have been performed in sooty mangabeys naturally infected with SIVsmm and in disease-susceptible rhesus macaques experimentally infected with SIVsmm. Data on virological studies demonstrate that the naturally infected sooty mangabeys are infected predominantly with SIV that have nef sequences distinct from those shown to cause disease in the inappropriate host, a factor which may contribute to disease resistance. Hyperimmunization with a variety of antigens or chronic infection contributes to accelerated disease and death in rhesus macaques if hyperimmunizations are initiated at the time of SIV infection, whereas similar hyperimmunization and chronic infection do not lead to disease in naturally infected 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 infected nonhuman primates. Immunological studies concerning changes in subsets of T cells, based on cytokine profile (TH0/TH1/TH2), showed that whereas rhesus macaques early post SIV infection show a dominant TH1 profile, this profile rapidly changes to TH0. On the other hand, mangabeys continuously demonstrate a TH2-like profile. Studies also showed 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 ELISA seronegative mangabeys. Although cells from SIV-infected mangabeys fail to show increased levels of apoptotic cells following incubation with immobilized anti-CD3, PBMC from rhesus macaques at varying time intervals 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 macaques 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 infection do have profound effects on the expression of a number of costimulatory and adhesion molecules. There appear to be differences in the nature of the intracellular phosphorylated proteins in cells from activated 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 infected sooty mangabeys. These findings can be employed for evaluating a nonvirus sterilizing form of SIV/HIV vaccines.