Immunopathogenesis of immune reconstitution disease in HIV patients responding to antiretroviral therapy

Abstract

Purpose of review: The aim of this article is to review the most recent literature regarding the immunopathogenesis of pathogen-associated immune reconstitution disease and to discuss the role of immune activation and various effector molecules and cells such as macrophages, effector and regulatory T cells, and natural killer cells in immune reconstitution disease.

Recent findings: Many HIV patients receiving antiretroviral treatment develop immune reconstitution disease, which is characterized by exaggerated inflammatory immune responses to replicating or dead pathogens. In the majority of these cases, immune reconstitution disease is associated with restoration of pathogen-specific cellular immune responses involving CD4 or CD8 effector T cells. The precise conditions that trigger immune reconstitution disease have not yet been identified. Immune reconstitution disease patients have overt immune activation, which may be due to poor homeostatic control after the fast initial immune recovery in patients receiving antiretroviral therapy. Poor homeostatic control in immune reconstitution disease patients may be linked to unbalanced restoration of effector and regulatory T cells.

Summary: Although the precise mechanism of immune reconstitution disease is not well understood, it is probably related to rapid restoration of pathogen-specific immune responses and poor homeostatic control that promote exaggerated immunopathological responses, especially if viable pathogens or pathogen debris are present at high concentrations.

Figure 1. The immunopathogenesis of immune reconstitution disease is not precisely known but there are indications that various players are involved

CD4 T cells (1) are involved in mycobacterial and other granulomatous immune reconstitution disease (IRD) whereas CD8⁺ T cells (2) are more frequently associated with viral IRD. IRD could be the consequence of unbalanced reconstitution of overactivated T cells and regulatory T cells (Tregs) (3). Direct activation of monocytes (4) and dendritic cells (5) during immune reconstitution, in particular by living or dead mycobac-teria or antigenic debris could be a possibility (6). Antigen load (6) during immune restoration may be a determining factor as well. Finally, the cytokine environment (7) during immune restoration, IL-7 and IL-10 in particular, both important in T-cell homeostasis, could have a pivotal role in the IRD. MTB, Mycobacterium tuberculosis; Mϕ, macrophage.