Generalized immune activation and innate immune responses in simian immunodeficiency virus infection

Abstract

Purpose of review: Chronic immune activation is a key factor driving the immunopathogenesis of AIDS. During pathogenic HIV/simian immunodeficiency virus (SIV) infections, innate and adaptive antiviral immune responses contribute to chronic immune activation. In contrast, nonpathogenic SIV infections of natural hosts such as sooty mangabeys and African green monkeys (AGMs) are characterized by low immune activation despite similarly high viremia. This review focuses on the role of innate immune responses in SIV infection.

Recent findings: Several studies have examined the role of innate immune responses to SIV as potential drivers of immune activation. The key result of these studies is that both pathogenic SIV infection of macaques and nonpathogenic SIV infections of natural hosts are associated with strong innate immune responses to the virus, high production of type I interferons by plasmacytoid dendritic cells, and upregulation of interferon-stimulated genes (ISGs). However, SIV-infected sooty mangabeys and AGMs (but not SIV-infected macaques) rapidly downmodulate the interferon response within 4-6 weeks of infection, thus resulting in a state of limited immune activation during chronic infection.

Summary: Studies in nonhuman primates suggest that chronic innate/interferon responses may contribute to AIDS pathogenesis. Further, the ability of natural host species to resolve innate immune responses after infection provides a novel avenue for potential immunotherapy.

Figure 1. Transcriptional profiles of pathogenic and nonpathogenic SIV infection

(A) Virological and immunological parameters of prototypical SIV infection in natural host species contrasted with pathogenic infections. Solid lines denote natural hosts, transparent lines depict macaque species. Kinetics of viral loads are similar between species. In general, natural hosts do not undergo rapid peripheral CD4+ T lymphocyte depletion as observed in macaques; it should be noted that in a handful of natural hosts, CD4+ depletion has been observed in the absence of disease [–53], and that long term SIV infection of sooty mangabeys is associated with a gradual, although clinically benign, decline of blood CD4+ T cells [54]. Immune activation as assessed by peripheral blood CD8+Ki67+ levels occurs in both animals during acute SIV infection [–56], but returns to near-baseline levels after infection, in contrast to macaque species, which remain elevated. Transcriptional regulation in (B) natural host and (C) macaque species during SIV infection. Both species have massive upregulation of interferon stimulated genes (ISGs) during acute infection (depicted by red lines); during the transition to chronic phase the ISG response resolves in natural hosts but is maintained indefinitely in macaques. mRNAs for multiple restriction factors (blue lines) are present in blood during acute infection of both species but decline rapidly. Genes associated with negative regulation of the immune response (green lines) are expressed differentially between species.

Figure 2. Potential mechanisms of resolution of ISG response in natural hosts during SIV infection

CD123+ Plasmacytoid DCs are the primary producers of IFNα in LNs of SIV-infected RMs, AGMs and SMs [46]. During chronic infection, pDCs in natural host species stop producing IFNα, concurrent with the resolution to baseline of ISG expression, despite continued high level viremia. Possible mechanisms by which the resolution occurs are (A) Immunoregulatory: transcript profiling data demonstrated elevated expression of immunomodulatory proteins such as ADAR and IDO in SMs; alternatively negative regulation of IFNα production in pDCs by ITAM mediated pathways has been demonstrated in mice, but data are lacking in the context of pDC/HIV interactions. (B) DC-specific HIV Restriction: Recent data has demonstrated that productive infection of DCs by HIV is blocked by an uncharacterized restriction factor [57]; circumvention of DC restriction yields a high level of virus production and secretion of Type I IFNs. During acute infection there is widespread induction of restriction factors, and inhibition of DC infection may remove the nidus for IFNα production. (C) Reduced mucosal homing - pDCs in natural hosts have attenuated recruitment to vaginal and rectal mucosa in comparison with macaques during chronic infection. Lowered gut homing may reduce pDC exposure to sites of high level virus replication, and limit their potential for driving immune activation in mucosal lymphoid tissue. (D) Dysregulated pDC Desensitization/Maturation - Recent work has shown that HIV, unlike other viruses recognized by pDC TLRs, signal predominately in early endosomes, resulting in partially mature pDCs that have a continual ability to make IFNα and poor expression of costimulatory molecules[39]. pDCs in natural hosts may have altered interactions with SIV that allow for full maturation and cessation of interferon production.