Systems biology of natural simian immunodeficiency virus infections

Abstract

Purpose of review A key factor driving AIDS-associated immunopathogenesis is chronic immune activation. SIV infection of African natural host species leads to high viremia, but low immune activation and absence of disease. Considerable progress in our understanding of pathological immune activation have come from comparative studies of SIV infection in pathogenic Asian macaque species and natural hosts. The focus of this review is to highlight recent work on the natural host model using high throughput genomics. Recent findings Several groups have independently conducted microarray gene expression profiling comparing in vivo SIV infection in natural and non-natural hosts. A consistent finding between these studies is that both pathogenic SIV infection of macaques and nonpathogenic infections of natural hosts have strong induction of interferon-stimulated genes (ISGs) early on, but a key difference was that natural hosts downmodulated the interferon response rapidly after acute infection. The development of new genome-based resources for further study of the natural host model is discussed. Summary Initial efforts using high throughput biology to study SIV infection of natural hosts have effectively identified the ability of natural hosts to resolve interferon responses and immune activation. Further application of ‘omic’-based technologies coupled with integrative systems-based analysis should continue to yield progress.

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

“…The much greater age of the "natural host" epidemics in African monkeys, and in sooty mangabeys in particular (90), is consistent with the greater extent of silent mutations we observed in SIVsmm, and it would furthermore allow the evolution of higher degrees of viral tolerance (virus/host coevolution for reduced pathogenicity). Sooty mangabeys, like African green monkeys, rarely progress to AIDS despite high-intensity SIVsmm infection; one mechanism by which tolerance is achieved in mangabeys is reduced immune activation (8,15,16,74). Rates of progression to AIDS are associated with chronic immune activation (24), and the failure to downregulate interferon-stimulated genes after acute infection appears to be restricted to the pathological infections that occur in macaques and humans (8).…”

“…Sooty mangabeys, like African green monkeys, rarely progress to AIDS despite high-intensity SIVsmm infection; one mechanism by which tolerance is achieved in mangabeys is reduced immune activation (8,15,16,74). Rates of progression to AIDS are associated with chronic immune activation (24), and the failure to downregulate interferon-stimulated genes after acute infection appears to be restricted to the pathological infections that occur in macaques and humans (8). In any case, the combined immunological and natural selection data argue strongly that the nonpathogenicity of SIVsmm in mangabeys is not due to a more effective immune response, and SIVsmm diversity appears to have evolved under lower immune pressure than HIV-1 diversity.…”

Loss of a Tyrosine-Dependent Trafficking Motif in the Simian Immunodeficiency Virus Envelope Cytoplasmic Tail Spares Mucosal CD4 Cells but Does Not Prevent Disease Progression

“…Alternatively, host-specific differences in the kinetics, magnitude, and anatomic sites of infection and coordination between early innate and later adaptive immune responses have been proposed to play key roles leading to the tolerance of viral replication seen in nonpathogenic hosts in contrast to the sustained and ultimately deleterious immune responses of the pathogenic host (49,(62)(63)(64)(65). As noted above, given that ⌬GY-infected animals progressed to AIDS with chronic immune activation in the absence of early gut damage, it is likely that alternative drivers of this sustained host immune response are responsible.…”

Insights from natural host–parasite interactions: The Drosophila model

“…For example, natural hosts of simian immunodeficiency virus (SIV) display non-progressive infections and do not develop immunodeficiency, whereas non-natural primate hosts cannot control SIV progression. Genetic analyses have uncovered differences in the molecular underpinnings of the natural and non-natural host responses (Bosinger et al, 2012). These differences were found to be clinically relevant, as a group of human immunodeficiency virus (HIV)-infected humans that display a non-progressive immune reaction to HIV possess transcriptional responses to infection that more closely mirror those of natural (non-progressive) hosts of SIV (Rotger et al, 2011).…”