What can natural infection of African monkeys with simian immunodeficiency virus tell us about the pathogenesis of AIDS?

The simian immunodeficiency viruses are a diverse group of viruses that naturally infect a wide range of African primates, including chimpanzees, African green monkeys (AGM) and sooty mangabey monkeys (SM). Although natural infection is widespread in feral populations of AGMs and SMs, this infection does not result in immunodeficiency. However, experimental inoculation of Asian macaque species results in an immunodeficiency syndrome that is remarkably similar in pathogenesis to human AIDS. Thus, SIVsm infection of macaques results in AIDS, and similarly experimental inoculation of pigtailed macaques with at least one SIVagm isolate, SIVIhoest or SIVsun, results in AIDS. The extent of plasma viremia in pathogenic infection is an excellent prognostic indicator of clinical course, with higher viral load being predictive of shorter survival and low viremia being predictive of long-term non-progression. Based upon this paradigm, one would have expected naturally infected animals to exhibit low levels of viremia. In reality, AGMs, SMs, mandrills and chimpanzees infected naturally with their own unique viruses display moderate to high levels of plasma viremia. A significant reduction in CD4+ T-cells in infected versus uninfected SMs suggests that the virus may be cytopathic to some degree. These infected animals still maintain adequate CD4+ T-cells over their entire life in captivity. A distinct characteristic of natural infection is the lack of immunopathology as demonstrated by normal lymph node morphology, lower expression of activation and proliferation markers on CD4+ T-cells, and a generally muted immune response to the virus. Naturally infected SMs and AGMs clearly mount antiviral cellular and humoral immune responses. Therefore, models suggesting immune tolerance to SIV are far too simplistic to explain the lack of disease in these animals. It is probable that a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death has been achieved in SMs and AGMs. The study of the dynamics of T-cell production, proliferation and cell death in asymptomatic natural infection should, therefore, yield insights into the pathogenesis of AIDS.