Chronic innate immune activation as a cause of HIV-1 immunopathogenesis

Abstract

Human immunodeficiency virus (HIV)-1 infection causes progressive impairment of the immune system in humans, characterized by depletion of CD4 T cells and loss of T cell function. Increased markers of T cell activation and lymphoid hyperplasia suggest that chronic T cell activation persists in immunocompromised hosts, and contributes to the exhaustion of immune functions. Here we propose a revision of this hypothesis, in which we suggest that chronic activation of innate immunity may negatively affect adaptive T cell-mediated responses. We hypothesize that constant exposure of the effector cells of innate immunity to HIV results in their chronic hyperactivation, with deleterious effects on T cells. In particular, plasmacytoid dendritic cells (pDC) may be highly susceptible to HIV-induced activation due to its interaction with the cellular receptor CD4, expressed by pDC. Subsequent production of type I interferon and indoleamine 2,3-dioxygenase may exert suppressive and cytotoxic effects on T cells.

Figure 1. Chronic innate immune activation as a cause of chronic T cell activation and functional impairment

(A) During most viral infections, early innate immune responses promote and are replaced by efficient adaptive T cell responses, ultimately resulting in the clearance or control of the infectious agent. (B) HIV/SIV infection of natural resistant hosts is not efficiently cleared by immune responses, but the immune system appears to respond normally to the infection, and no signs of chronic immune activation or immune deficiency are observed. (C) We hypothesize that HIV/SIV infection of susceptible hosts results in abnormal and prolonged activation of innate immune responses, resulting in: 1) induction of phenotypic markers of T cell activation, such as CD38 and the lymphoadenopathy syndrome (LAS); 2) progressive T cell depletion through apoptotic mechanisms; and 3) suppression of functional T cell responses by mechanisms such as IDO/Treg or PDL-1.