Immune activation and collateral damage in AIDS pathogenesis

Abstract

In the past decade, evidence has accumulated that human immunodeficiency virus (HIV)-induced chronic immune activation drives progression to AIDS. Studies among different monkey species have shown that the difference between pathological and non-pathological infection is determined by the response of the immune system to the virus, rather than its cytopathicity. Here we review the current understanding of the various mechanisms driving chronic immune activation in HIV infection, the cell types involved, its effects on HIV-specific immunity, and how persistent inflammation may cause AIDS and the wide spectrum of non-AIDS related pathology. We argue that therapeutic relief of inflammation may be beneficial to delay HIV-disease progression and to reduce non-AIDS related pathological side effects of HIV-induced chronic immune stimulation.

Keywords: AIDS; Immunity; TLR; immune activation; pathogenesis; therapy.

Figure 1

Pathways of chronic immune activation and its down-stream effects in HIV infection. HIV infection induces chronic immune activation through activation of the innate and the adaptive immune system, via single-stranded (ss) RNA and possibly through intracellular viral DNA which activate pDCs via endosomal TLR7 and 8. This activation leads to the induction of IFNα via the IRF-7 pathway and the induction of IL-6, IL-12, TNFα, and TGFβ through the NF-κB pathway. Continuous activation of the lymphocyte compartment leads to attrition of the T-cell pool (14, 15) and “immune paralysis” (e.g., impaired CTL responses). Bacterial translocation may be another source of TLR activation via TLR2, 4, 5, and 9 (–51). Over time also non-AIDS related complications develop. Potential targets for therapeutic interventions with inflammation to diminish pathology are indicated. It has been shown that blocking the effect of TLR7 and 9 significantly reduces HIV-induced immune activation (124). Studies in pathogenic and non-pathogenic SIV infection suggest that blocking IRF-7 or IFNα should be investigated. In rheumatoid arthritis patients who were treated with TNFα inhibiting agents (infliximab, etanercept) it was shown that blocking the effect of TNFα reversed the increased incidence of cardiovascular complications and insulin resistance. In analogy, the potential for a therapy interfering with TNFα in HIV infection should be tested (–127).