Nature review: Type I interferons and AIDS

Viruses have evolved highly effective mechanisms to manipulate the host immune response and facilitate replication. Following HIV infection in humans or simian immunodeficiency virus (SIV) infection in rhesus macaques, a chronic activation of the innate immune system is observed. This immune response is triggered by the recognition of viral RNA and DNA by members of the Toll-like receptor (TLR) family, specifically TLR7 and TLR9 on plasmacytoid dendritic cells (pDCs). These cells are also known as interferon (IFN)-producing cells due to the massive quantities of IFNa secreted following stimulation. One outcome of this chronic inflammation is a reduction in the regenerative ability of CD4+ T cells. This effect results in significant T cell depletion and is a major contributor to immunodeficiency associated with AIDS.

However, it now appears that divergent host immune responses can also result in different outcomes to the same virus. For example, in contrast to rhesus macaques, sooty mangabeys do not progress to AIDS following SIV infection, but instead act as a reservoir host for the virus. A recent paper in Nature Medicine by Mandl et al (1) examined the differences in the immune response to SIV in both sooty mangabeys and rhesus macaques in order to understand the mechanisms contributing to AIDS progression. Although viral replication was comparable in both species, minimal T cell and NK cell proliferation was observed in the sooty mangabeys following SIV infection, as opposed to high cell proliferation and expansion in the rhesus macaques. In addition, pDC activation was increased in the rhesus macaques but not in the sooty mangabeys, as measured by expression of the chemokine receptor CCR7, a reliable marker of pDC migration to lymph nodes (1). These results show a significant attenuation of the immune response to SIV infection in the sooty mangabeys, suggesting that the lack of AIDS progression in this species is a result of specific immune response mechanisms, as opposed to properties inherent to the virus itself.

Figure from O'Connell and Siliciano (2).

The authors next investigated TLR7 and TLR9 responses to SIV in peripheral blood mononuclear cells (PBMCs) from humans, rhesus macaques and sooty mangabeys. Despite high IFNa production in humans and rhesus macaques, they found much lower secretion of IFNa from sooty mangabeys (1). However, this effect was not limited to SIV infection, as reduced IFNa production was also observed when PBMCs from sooty mangabeys were stimulated with a panel of TLR7 and TLR9 ligands. Interestingly, the ability of sooty mangabey PBMCs to produce the proinflammatory cytokines TNFa and IL-12 was not diminished, implying that TLR7 and TLR9 recognition of SIV is normal in these cells, but that there is a deficiency in the downstream pathways leading to type I IFN production (1). The researchers suggest that this deficiency may lie at the level of interferon regulatory factor 7 (IRF7), the critical transcription factor for type I IFN production. They come to this conclusion following sequence analysis of genes encoding prominent members (including TLR7, TLR9, MyD88, IRF7 and several type I IFN promoters) of the TLR7 and TLR9 pathways in humans, rhesus macaques and sooty mangabeys. Whilst most genes were highly conserved, several polymorphisms were found in the sooty mangabey IRF7 coding sequence. The authors speculate that these polymorphisms, which cause amino acid substitutions in the transactivation domain of IRF7, may be responsible for the deficiency in type I IFN signaling, and consequently the protection against AIDS.

This study has provided an interesting new insight into the immune mechanisms contributing to the progression of AIDS. Specifically, it appears that IRF7 polymorphisms resulting in the attenuation of the type I IFN response in sooty mangabeys protects against the development of AIDS. These mutations have been preserved in sooty mangabeys as they offer an evolutionary advantage, namely a reduced susceptibility to immunodeficiency disease. This implies that the pathogenesis of AIDS in susceptible species may be a combination of both viral replication and prolonged immune activation. Based on this research, a potential therapeutic strategy to combat AIDS would involve inhibiting virus binding to CD4 on pDCs, thus attenuating cell proliferation. In addition, the inhibition of excessive type I IFN release by pDCs may prove to be beneficial, either through the use neutralising IFNa antibodies or by specifically targeting IRF7. However, these potential strategies are not without limitations, as an inhibition of type I IFN production would leave a patient dangerously immunocompromised. Instead, more research into the contribution of innate immune mechanisms to AIDS progression may result in the use of specific inhibitors as part of a combinatorial therapeutic approach.

(1) Mandl et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med. 2008 Oct;14(10):1077-87.

(2) O'Connell and Siliciano. Immune alteration fends off AIDS. Nat Med. 2008 Oct;14(10):1016-8.