Biomarkers of HIV Immune Reconstitution Inflammatory Syndrome

Abstract

Dysregulation of the immune system drives HIV pathogenesis. As we develop new ways to treat HIV and AIDS, we encounter new clinical ramifications of our treatment on regulatory components of the immune system. HIV-associated Immune Reconstitution Inflammatory Syndrome (IRIS) occurs after initiation of anti-retroviral therapy (ART) with inappropriate and dysbalanced restoration of the immune system resulting in pathologic inflammatory reactions with significant morbidity. IRIS is most commonly associated with latent, occult, or past infections, including tuberculosis, Cryptococcus neoformans, and Mycobacterium avium-complex. We discuss common clinical presentations, new diagnostic modalities, current hypotheses of IRIS pathogenesis, and future directions of IRIS-related research, focusing on the identification of biomarkers that can be used to predict and diagnose IRIS.

Figure 1

The conditions for IRIS are a complex interplay between host and pathogen. The recovery of the host’s immune system is critical to IRIS pathogenesis. With ART, persons gradually reconstitute their antigen-specific immunity to a pathogen (Shaded in Gray). Yet, the timing of reconstitution of T-cell subsets is variable. During reconstitution, the normal 2:1 balance between the pro-inflammatory (Th-17 subset) and the anti-inflammatory (T-regulatory subset) of the immune system (Dashed Line) may become unbalanced leading to the possibility of dysregulated responses. Secondly, following an infection, antigen clearance is variable (Solid Line). Pathogens with rapid antigen clearance are less likely to generate an IRIS event, such as pneumococcal pneumonia. However, pathogens, such as TB and cryptococcus, in which antigens persist for months are at higher risk of developing IRIS (~33%). Overall, with HIV therapy, the immune system’s reversal from an anergic state in the presence of abundant antigen and in the absence of normal homeostatic regulatory mechanisms create the potential for an IRIS event.

Figure 2

Immune cells normally interact in a state of homeostasis mediated by T regulatory cells (T_REGs). Alteration in the balance between these components of the immune system and in their functionality may lead to IRIS. Adapted from Kestens et al.[26].