Into the wild: simian immunodeficiency virus (SIV) infection in natural hosts

Abstract

Identifying distinctions between pathogenic HIV and simian immunodeficiency virus (SIV) infections and nonprogressive SIV in natural African primate hosts might provide key insights into HIV pathogenesis. Similar to pathogenic HIV infection in humans, natural SIV infections result in high viral replication and massive acute depletion of mucosal CD4(+) T cells. A key distinction of natural SIV infections is a rapidly developing anti-inflammatory milieu that prevents chronic activation, apoptosis and proliferation of T cells and preserves the function of other immune cell subsets, thus contributing to the integrity of the mucosal barrier and the lack of microbial translocation from the gut to the peritoneum. Immunologic features observed during natural SIV infections suggest approaches for designing new strategies for producing novel second-generation vaccines and therapeutic approaches to inhibit disease progression in HIV-infected humans.

Figure 1. Comparison of major parameters of SIV infections in natural hosts and HIV-1 infection in humans

a. The levels of viral replication are similar between naturally-infected non-human primates (NHP) and HIV-1-infected patients. The major difference occurs in the late stage of the chronic infection, when the steady state is maintained in natural SIV infection but viral loads increase in HIV-1-infected patients with consequent disease progression. b. The dynamics of peripheral CD4⁺ T-cells, as well as mucosal (intestinal) CD4⁺ T-cells is generally similar during acute infection in both natural and pathogenic types of infection. During the chronic phase (right hand panels in each group), there is a partial restoration in naturally infected group resulting in the stabilization of the mucosal CD4⁺ T-cell pool, while in pathogenic HIV infection, a partial restoration occurs only in the initial stages, and CD4⁺ T-cell depletion continues to exhaustion with disease progression. c. There are no significant differences in humoral immune responses (illustrated here by total anti-HIV or SIV antibody and neutralizing antibody titers) or cellular immune responses (measured by IFN-γ ELISPOT). Both humoral and cellular immune responses are slightly lower in natural infections compared to pathogenic HIV-1 infection. Plots are synthesized from papers published both by ourselves and others and indicate average values.

Figure 2. Major differences observed between non-pathogenic natural SIV infections and pathogenic SIVmac infection of rhesus macaques, prevent disease progression in natural hosts and result in disease progression in SIVmac-infected macaques

An anti-inflammatory milieu (illustrated here by the dynamics of IL-10 and Fox-P3, a T-regulatory cell marker) is rapidly installed in natural hosts after SIV infection (starting from day 1 post-infection). As a result, the levels of immune activation (illustrated here by the levels of HLA–DR expression on both CD4⁺ and CD8⁺ T-cells), T-cell proliferation (illustrated by the levels of Ki-67⁺ CD8⁺ T-cells) and apoptosis of CD4⁺ T-cells in the intestine are relatively well controlled in natural infections (a). Pro-inflammatory cytokines (illustrated by the dynamics of IFN-γ in plasma) are only transiently increased at low levels (b). As a consequence, the integrity of the mucosal immunological barrier is maintained (as illustrated by the dynamics of plasma LPS levels) (c), which in turn prevents chronic immune activation and disease progression. In pathogenic SIVmac infection of rhesus macaques, a pro-inflammatory milieu results in excessive immune activation, apoptosis and T-cell proliferation, generating severe damage of the mucosal barrier and microbial translocation which maintains the chronic immune activation and results in disease progression. Cellular markers are presented as percentages of the major T-cell population. Soluble read-outs such as cytokines (ng/ml) and LPS (pg/ml) are presented as plasma concentrations. Fox-P3 gene expression is shown as the fold increase within peripheral blood monocytes (PBMCs). Plots summarize data from previously published papers from ourselves and others and represent average values.

Figure 3. Comparison of events associated with natural SIV infection and pathogenic SIV and HIV-1 infection

Differences in host response to infection are responsible for the outcome of the infection: a balanced host response in natural infection (left hand side) shuts down most of the factors that have deleterious consequences for the infected hosts (immune activation, apoptosis, excessive inflammation, enteropathy). In pathogenic infections, excessive host responses result in mucosal damage and consequent translocation of gut microbial products, immune system exhaustion and progression to AIDS (right hand side). Red boxes indicate deleterious events whereas green boxes beneficial ones.