Perturbations of Cell Cycle Control in T Cells Contribute to the Different Outcomes of Simian Immunodeficiency Virus Infection in Rhesus Macaques and Sooty Mangabeys

Abstract

In contrast to human immunodeficiency virus (HIV) infection of humans and experimental simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs), SIV infection of sooty mangabeys (SMs), a natural host African monkey species, is typically nonpathogenic and associated with preservation of CD4+ T-cell counts despite chronic high levels of viral replication. In previous studies, we have shown that the lack of SIV disease progression in SMs is related to lower levels of immune activation and bystander T-cell apoptosis compared to those of pathogenic HIV/SIV infection (G. Silvestri, D. Sodora, R. Koup, M. Paiardini, S. O’Neil, H. M. McClure, S. I. Staprans, and M. B. Feinberg, Immunity 18:441-452, 2003; G. Silvestri, A. Fedanov, S. Germon, N. Kozyr, W. J. Kaiser, D. A. Garber, H. M. McClure, M. B. Feinberg, and S. I. Staprans, J. Virol. 79:4043-4054, 2005). In HIV-infected patients, increased T-cell susceptibility to apoptosis is associated with a complex cell cycle dysregulation (CCD) that involves increased activation of the cyclin B/p34-cdc2 complex and abnormal nucleolar structure with dysregulation of nucleolin turnover. Here we report that CCD is also present during pathogenic SIV infection of RMs, and its extent correlates with the level of immune activation and T-cell apoptosis. In marked contrast, naturally SIV-infected SMs show normal regulation of cell cycle control (i.e., normal intracellular levels of cyclin B and preserved nucleolin turnover) and a low propensity to apoptosis in both peripheral blood- and lymph node-derived T cells. The absence of significant CCD in the AIDS-free, non-immune-activated SMs despite high levels of viral replication indicates that CCD is a marker of disease progression during lentiviral infection and supports the hypothesis that the preservation of cell cycle control may help to confer the disease-resistant phenotype of SIV-infected SMs.

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

“…Therefore, it is conceivable that these B cell subsets are partially responsible for the hypergammaglobulinemia observed during chronic SIV infection in RhMs. The lack of hypergammaglobulinemia and the restoration of total and memory B cell subsets, in addition to the well-described resolution of immune activation in AGMs during the early stages of SIV infection (65)(66)(67), support the notion that natural hosts lack the B cell dysfunction that likely impairs antibody responses during pathogenic SIV infection. We also identified several differences in the B cell populations and immunoglobulin content in milk of SIV-infected AGMs and RhMs.…”

Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys

“…The most intriguing feature of naturally SIVinfected SMs is that, unlike HIV/SIV-infected humans and RMs, these animals typically remain asymptomatic and do not progress to AIDS despite levels of plasma viremia that are as high, or even higher, than those observed in HIV-infected patients (14,15). Although the mechanism(s) underlying the lack of disease progression in SMs is still unknown, our previous studies have shown that a characteristic feature of this infection is the overall preservation of peripheral blood (PB) CD4 ϩ T cell homeostasis that occurs in the absence of the chronic immune activation, bystander T cell apoptosis, and cell cycle dysregulation that are associated with pathogenic primate lentiviral infections (15)(16)(17)(18)(19).…”

Correlates of Preserved CD4+ T Cell Homeostasis during Natural, Nonpathogenic Simian Immunodeficiency Virus Infection of Sooty Mangabeys: Implications for AIDS Pathogenesis

“…Based on a series of previous studies conducted in relatively small cohorts of naturally and experimentally SIV-infected SMs, we proposed that attenuated immune activation may be instrumental in maintaining the AIDS-free state of these animals (11,17,28). From an evolutionary perspective, these studies suggested that SMs (and perhaps other natural hosts for SIV) have adapted to the selective pressure of SIV infection and have reached a disease-free equilibrium that does not require strict control of viral replication (with viral loads that are as high if not higher than those seen during pathogenic HIV infection) but instead results from a general attenuation of the overall level of immune activation.…”