Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy.

Jinchuan Shi,Jie Wu,Zhongdong Zhang

doi:10.1155/2022/3179200

Abstract

Human immunodeficiency virus (HIV) infection is characterized not only by severe immunodeficiency but also by persistent inflammation and immune activation. These characteristics persist in people living with HIV (PLHIV) receiving effective antiretroviral therapy (ART) and are associated with morbidity and mortality in nonacquired immunodeficiency syndrome (AIDS) events. ART can inhibit HIV replication and promote immune reconstitution, which is currently the most effective way to control AIDS. However, despite effective long-term ART and overall suppression of plasma HIV RNA level, PLHIV still shows chronic low-level inflammation. The exact mechanisms that trigger chronic inflammation are unknown. Activation of the inflammasome is essential for the host response to pathogens, and some recent studies have confirmed the role of the inflammasome in the pathogenesis of inflammatory diseases. The NLRP3 inflammasome has been widely studied, which is a pyrin domain-containing protein 3 belonging to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent studies suggest that inflammasome-mediated pyroptosis is associated with CD4+ T cell loss in the absence of persistent infectious HIV replication. This article reviews the mechanism of the NLRP3 inflammasome and its correlation with immune reconstitution in PLHIV treated with ART.

Highlights

Various mechanisms have been proposed to explain the death of these bystander cells, including host factors [4] and various viral factors released from infected cells (e.g., Human immunodeficiency virus (HIV)-1Tat, Vpr, and Nef) [5]
In macrophages and animal models of type 2 diabetes, hyperglycemia and free fatty acids can trigger inflammasome activation, impairing glucose metabolism and enhancing insulin resistance [22]. These findings suggest that accumulation of abnormal metabolites activates the NLRP3 inflammasome during the progression of metabolic diseases
Further studies have shown that MCC950 acts on the NLRP3 inflammasome but not on the NLRP1, AIM2, or NLRC4 inflammasome. These findings raise the possibility of novel “anti-HIV” therapies targeting the host rather than the virus. Such novel anti-HIV therapies, which are aimed at altering host tolerance to the virus rather than inhibiting viral replication, may be beneficial in (1) patients with broad-spectrum resistance or limited access to antiretroviral therapy (ART), (2) blocking the earlier onset of age-related chronic inflammatory diseases that may lead to HIV infection, and (3) acting as a potential treatment of HIV

Summary

Possible Mechanism of CD4+ T Cell Depletion Induced by Human Immunodeficiency

Laboratoryadapted HIV strains lead to productive infection and apoptotic death in CD4+ T cells These activated CD4+ T cells appear to be too limited to explain the substantial loss of CD4+ T cells observed in vivo [2]. Monocyte-derived macrophages produce the virus within a few weeks [8], and infected microglia appear to survive for months or even years [9]. These findings suggest that viral infection and replication are not intrinsically linked to cell death. The cell death observed in HLAC involves abortive viral infection in resting CD4+ T cells, not driven by membrane signaling events via CD4 or chemokine coreceptors nor the elaboration of cytotoxic viral proteins or host factors [12]. Death is the result of a strong defensive innate immune response initiated by the host to the virus, leading to “cellular suicide” rather than “viral murder.”

Role of the NLRP3 Inflammasome in Inflammatory Diseases

Relationship between Chronic Inflammation and Immune Reconstitution in People

Findings

Conclusion