Lessons learnt from studies of the immune characterization of naturally SIV infected Sooty Mangabeys

Abstract

The vast number of African non-human primates species that are naturally infected with the simian immunodeficiency viruses ( SIV) but have not shown any signs of lentivirus associated disease as compared to the Asian non-human primate species that do not demonstrate any detectable signs of lentiviral infection but who upon experimental infection with select SIV isolates from the African species develop clinical signs and laboratory based findings similar to human HIV-1 infection provide a powerful model to define virus-host relationships. It is our belief that unraveling those differences which are specifically associated with disease resistance and/or disease susceptibility culled out from those that are species specific differences unrelated to disease outcome may provide some important insights which maybe fruitful for the formulation of vaccine strategies. The purpose of this chapter is to provide the reader with a summary of the findings from our laboratory from the past decade using the naturally SIV infected sooty mangabey model aimed at ferreting out some of these differences. Some very important paradoxes exist with this naturally infected lentivirus model. Thus, it is difficult to determine why these species demonstrate highly effective immune responses but yet maintain very high viral loads. Why do these naturally SIV infected species not demonstrate the plethora of clinical symptoms ascribed to select proteins of the SIV such as 'tat', 'nef', and other viral proteins as do the rhesus macaques and humans to HIV? Most of the targets of such proteins are highly conserved and yet no detectable pathology? We submit that the naturally infected species has evolved over time with a highly regulated immune system (a perfect host/parasite relationship) that is sufficient to prevent pathology and not in the order to exhaust the immune system. In addition, the quality of the anti-viral immune response is of interest. Thus, the mangabeys demonstrate a clear skew in their cytokine based immune response towards a predominantly TH2 bias which we believe is the reason why this species of mangabeys among the many studied, is perhaps is the only species that is susceptible to M. leprae infection (see Dr. B. Gormus's chapter). Some of our working hypotheses that are aimed to provide explanations for some of these paradoxes are provided herein.

Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS

“…We found no increase in LNLCs and BALCs and increases in PBMCs only between days 5 and 16 after infection. This is consistent with the decreased IFN-γ production in CD4 + T cells and low CTL frequencies reported in chronically SIVsm-infected SMs (11,12). It is beneficial to maintain a Th1-type cytokine secretion pattern when it is associated with efficient CTL responses during chronic HIV-1 infection, as observed in some LTNPs (26).…”

“…Naturally infected MNDs and SMs exhibit nearly unchanged percentages of CD4 + DR + T cells and only slight increase in the percentages of CD8 + DR + T cells in blood (10,11). Long-term SIVsm infection in SMs is characterized by normal T cell turnover and decreased IFN-γ expression that correlates with low CTL activity (8,11,12). Finally, chronically infected AGMs, SMs, and CPZs failed to show enhanced peripheral CD4 + T cell apoptosis levels (11,13).…”

“…It is beneficial to maintain a Th1-type cytokine secretion pattern when it is associated with efficient CTL responses during chronic HIV-1 infection, as observed in some LTNPs (26). Although, Th1 responses are protective, they may be harmful if they are associated with strong, generalized immune activation (12,27). An et al indeed reported that a TNF-α-inducible promoter variant of IFN-γ (-179T) accelerates loss of CD4 + T cells in humans (28).…”

Early Resolution of Acute Immune Activation and Induction of PD-1 in SIV-Infected Sooty Mangabeys Distinguishes Nonpathogenic from Pathogenic Infection in Rhesus Macaques

“…Because previous studies have clearly established that lower levels of immune activation and T cell proliferation are a major distinguishing feature of nonpathogenic infections (1,5,17,(22)(23)(24)(25), we investigated the potential underlying mechanisms of this difference by conducting a comparative analysis of the early stages of nonpathogenic infection of SMs and pathogenic SIV infection of RMs. By concentrating on the initial stages of infection and studying LT at multiple time points within the first 30 days of infection, we were able to uncover a significant, albeit transient, phase of immune activation and proliferation in SMs that was not detected in previous studies in which a more limited sampling was performed (17).…”

“…Although several published studies have described the immunological and virological differences and similarities between nonpathogenic SIV infection of natural hosts and pathogenic SIV infection of RMs, most of these studies have focused on the peripheral blood or on the chronic stage of infection (1,2,(5)(6)(7)(8)(9)(22)(23)(24)(25). In this study, we focused on acute infection, concentrating particularly on analyses of LT that we could obtain from experimental SIV infection in SMs.…”