Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs

Abstract

Antiretroviral therapy (ART) is a life-saving intervention in human immunodeficiency virus (HIV) infection. Immune restoration after ART dramatically reduces the incidence and severity of opportunistic diseases and death. On some occasions, immune restoration may be erratic, leading to acute inflammatory responses (known as immune reconstitution inflammatory syndrome) shortly after ART initiation, or incomplete, with residual inflammation despite chronic treatment, leading to non-infectious morbidity and mortality. We propose that ART may not always restore the perfect balance of innate and adaptive immunity in strategic milieus, predisposing HIV-infected persons to complications of acute or chronic inflammation. The best current strategy for fully successful immune restoration is early antiretroviral therapy, which can prevent acquired immunodeficiency syndrome (AIDS)-associated events, restrict cell subset imbalances and dysfunction, while preserving structural integrity of lymphoid tissues. Future HIV research should capitalize on innovative techniques and move beyond the static study of T-cell subsets in peripheral blood or isolated tissues. Improved targeted therapeutic strategies could stem from a better understanding of how HIV perturbs the environmental niches and the mobility and trafficking of cells that affect the dynamic cell-to-cell interactions and determine the outcome of innate and adaptive immune responses.

Fig. 1. Graphic depiction of the inflammatory environment of IRIS (top) during early ART and chronic residual inflammation (bottom) of long-term treated HIV

(A) In IRIS, there is a contracted T-cell pool consisting mainly of highly activated effectors and a high antigen burden due to the uncontrolled underlying opportunistic disease. The injured mucosa further increases the antigen exposure and innate system activation, while the fibrosis in the lymph nodes restricts access to homeostatic cytokines that are underutilized leading to death of naive T cells. Apoptotic microparticles further blunt the function of antigen-presenting cells. As HIV viremia resolves, the activated effector T cells emerge and encounter primed antigen presenting cells in a disrupted milieu that fosters dysregulated inflammatory responses, and release cytokines (IFN-γ, TNF-α, IL-2, IL-17) that drive tissue damage in organs with abundance of foreign antigen such as lungs, liver, lymph nodes, or the central nervous system. (B) In chronic treated HIV, significantly lower foreign antigen burden (no opportunistic disease, partially restored leaky gut), continuing low levels of chronic viral stimulation, in the presence of a fuller T-cell pool with lower levels of T-cell activation and lower homeostatic forces, maintain innate system activation with activated monocytes and high levels of IL-6, soluble tissue factor, D-dimer, and soluble CD14 causing predominantly chronic inflammation and vascular endothelial damage that in turn results in end organ disease in the heart, brain, kidney, and liver.