Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

Abstract

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

Keywords: HIV; immune reconstitution inflammatory syndrome (IRIS); mycobacteria; systemic inflammation.

Figure 1

Influence of antiretroviral therapy (ART) on systemic inflammation. (A) After HIV infection, patients exhibit high viral loads with a concomitant decrease in CD4⁺ T cell counts. Over the course of HIV infection, people living with HIV (PLWH) experience dysfunction in immune activation and T cell exhaustion, resulting in chronic systemic inflammation and coagulopathy. (B) Upon ART commencement, a gradual restoration of the antiviral immune responses occurs, resulting in increased CD4+ T cell counts and decreases in HIV viral load. This process is followed by diminished systemic inflammation and therefore improved prognosis of PLWH. (C) With immune reconstitution inflammatory syndrome (IRIS), there is initial clinical improvement, followed by significant deterioration marked by an increased level of inflammation.

Figure 2

Most common opportunistic infections related to IRIS in PLWH. The figure shows a network analysis of the published studies on IRIS in PLWH available through the NCBI Pubmed Database. The terms used were “immune reconstitution inflammatory syndrome” AND “HIV”. Nodes represent the type of pathogen and genus/species, while the size of edges represents the number of publications retrieved in the search (Date of the search: 10 November 2020).

Figure 3

Mycobacterium tuberculosis-HIV co-infection increases levels of cytokine and chemokines produced by activated macrophages, leading to macrophage recruitment to the site of infection. This mechanism increases the production of proinflammatory mediators, thereby increasing inflammatory responses with modulation of host redox metabolism that ultimately facilitates HIV replication.