A crucial element in the development of effective therapeutic and prophylactic strategies for AIDS is an experimental animal model in which the course of immunodeficiency virus infection parallels the pathogenesis of the human disease. Simian immunodeficiency virus (SIV) infection of macaques satisfies this criterion and is therefore a relevant model. Notably, SIV induces an immunodeficiency syndrome in infected macaques that is remarkably similar in pathogenesis to human AIDS. An important use of this animal model system is the detailed study of pathogenesis and viral determinants of disease since many studies of this type are not feasible in humans. Such investigations should allow us to determine how primate lentiviruses destroy the immune system of their hosts, and this understanding should facilitate the development of more rational therapeutic antiviral strategies.The purpose of this project is to investigate host and viral factors involved in variable disease progression in SIV-infected macaques. To investigate the role of host factors, we employed well-defined molecularly cloned viruses (SIVsmE543-3) to reduce the complexity of the inoculated virus as a contributing factor. We have recently shown that the susceptibility to SIV infection of primary PBMC in vitro varies significantly between individual macaques. Interestingly, the susceptibility phenotype correlates with the extent of in vivo viral replication following inoculation of these animals. To further investigate this phenomenon as a potential factor affecting disease progression, we characterized a cohort of six rhesus macaques for a susceptibility phenotype. This cohort has been challenged with SIVsmE543. One of the two highly susceptible macaques only developed a transient antibody and CTL response and was euthanized due to AIDS by 16 weeks. Two macaques of the intermediate phenotype had significant viremia and two macaques with a low degree of susceptibility had very low viremia (negative by SIV p27 antigen during primary infection). The two least susceptible animals have shown no evidence of disease progression and have maintained low plasma viremia. In contrast, the other three macaques have persistent high viremia and evidence of disease progression (i.e. declining CD4). In order to evaluate the magnitude of the immune defect in such animals, macaques were immunized with tetanus toxoid and Hepatitis A (Haverix). While two SIV-naive macaques and three SIV-infected macaques responded appropriately to these antigens, the rapid progressor failed to develop antibody to either antigen.We also evaluated the role of vpr and vpx in the pathogenesis and mucosal transmissibility of the acutely lethal SIVsmPBj. Deletion of the vpx gene attenuated the ability of the virus to replicate in macrophages and resting T cells. Despite the inability to productively infect macrophages in vitro, this virus was readily transmitted across the mucosal surface of the rectum. Sequential in situ studies on the rectum revealed that the earliest SIV-expressing cells (2 days) were CD3+ T lymphocytes. In addition, we observed local amplification of SIV at the site of inoculation prior to the widespread dissemination and expression of virus at other lymphoid sites. These studies suggest that there is no requirement for productive infection of nondividing cells such as macropahges or dendritic cells following mucosal infection. They also suggest that there may be a wider treatment window following mucosal exposure due to local amplification. - simian immunodeficiency virus, SIV, macaque monkeys, pathogenesis, AIDS
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