Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections

Abstract

Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4(+) T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4(+) T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-alpha in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

“…To determine whether A3G was unique or merely representative of many innate responses contributing to protection, we further assessed natural killer (NK) cells, type I IFN, IFN regulatory factors, IFN-induced MxA (29), CXCL9, IL-1β, TNFα, and Granzyme B expression levels in the mesenteric lymph nodes (MLN) (Fig. S3), and did not observe significant differences among the groups, whereas type I IFN and TNFα 4 weeks after the last boost were up-regulated in the vaccinated group adjuvanted with TLR agonists alone, which had one of the highest VLs, consistent with the recent finding of a deleterious role played by type I IFN in mediating immune activation (30). In contrast, the combination of TLR agonists and IL-15 resulted in lower type I IFN, suggesting that IL-15 counteracts this effect by a mechanism that remains to be explored.…”

Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients

“…39 Our data support the theory of activationinduced cell death being one mechanism of CD4 ϩ T-cell depletion in HIV infection, because susceptibility to pDC/TRAIL-mediated killing depends on the activation of CD4 ϩ T cells. This is underscored by our observation that the susceptibility of CD4 ϩ T cells depends on HIV viremia in vivo and/or activation of T cells in vitro.…”

Pulmonary arterial hypertension in patients treated with interferon

“…Similarly, it has been suggested that HIV infection could promote PAH through indirect mechanisms and release of inflammatory mediators or growth factors. There is a chronic production of IFNa in patients with HIV infection [30,31] and an increased IFN expression correlates with HIV disease progression [32]. It is interesting to note that the proportion of patients with HIV co-infection in our study is higher than it is usually observed in patients with chronic HCV infection [33].…”