HIV-associated chronic immune activation

Abstract

Systemic chronic immune activation is considered today as the driving force of CD4(+) T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by anti-retroviral therapy, with the extent of this residual immune activation being associated with CD4(+) T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4(+) T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation characteristic of human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to 'show AIDS the door', and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives.

Fig. 1. Proposed contributors to HIV-associated chronic immune activation

There are multiple molecular and cellular mechanisms by which HIV infection could induce generalized immune activation. Among these, as summarized in this cartoon, HIV replication; immunomodulatory functions of viral proteins and immunes response to the virus; immune responses to reactivated infections; loss of mucosal integrity with consequent microbial translocation; altered balance of critical CD4⁺ T-cell subsets; increased homeostatic proliferation in response to CD4⁺ T-cell depletion; increased production of pro-inflammatory molecules. Importantly, each mechanism may feed to the others, thus creating an uncontrolled positive feedback. Furthermore, it is likely that the relative contribution of each varies among HIV-infected individuals or in distinct stages of HIV-infection, as well as in naïve versus HAART-treated patients. Adapted from Steven Deeks, XIX International AIDS Conference, 2012.

Fig. 2. Model of events in lymph nodes that could be associated with loss of CD4⁺ T cells

Immune activation is associated with a production of chemokines that allow immune cells to be held in secondary lymphoid organs. The number of T cells and B cells increases transiently and further contribute to secretion of chemokines. Morevoer, HIV infection is characterized by infiltrations of CD8⁺ T cells into germinal centers and accumulation of Treg in the T zone of lymph nodes. Treg associated TGFβ production induces collagen deposition and fibrosis. The latter causes damage of the FRC resulting in reduced access of naive CD4⁺ T cells to IL-7 and increased cell death by apoptosis. A consequence of CD4⁺ T-cell loss is a decreased production of LTb, which is necessary for the FRC network. The attraction of cells also leads to the arrival of new target cells for the virus that fuels the vicious cycle. Treg, regulatory T cell; GC, germinal center; FDC, follicular dendritic cell; Tfh, T-follicular helper cell, FRC, fibroblastic reticular cell

Fig. 2. Model of events in lymph nodes that could be associated with loss of CD4⁺ T cells

Immune activation is associated with a production of chemokines that allow immune cells to be held in secondary lymphoid organs. The number of T cells and B cells increases transiently and further contribute to secretion of chemokines. Morevoer, HIV infection is characterized by infiltrations of CD8⁺ T cells into germinal centers and accumulation of Treg in the T zone of lymph nodes. Treg associated TGFβ production induces collagen deposition and fibrosis. The latter causes damage of the FRC resulting in reduced access of naive CD4⁺ T cells to IL-7 and increased cell death by apoptosis. A consequence of CD4⁺ T-cell loss is a decreased production of LTb, which is necessary for the FRC network. The attraction of cells also leads to the arrival of new target cells for the virus that fuels the vicious cycle. Treg, regulatory T cell; GC, germinal center; FDC, follicular dendritic cell; Tfh, T-follicular helper cell, FRC, fibroblastic reticular cell