Inflammatory and immunometabolic consequences of gut dysfunction in HIV: Parallels with IBD and implications for reservoir persistence and non-AIDS comorbidities

Abstract

The gastrointestinal mucosa is critical for maintaining the integrity and functions of the gut. Disruption of this barrier is a hallmark and a risk factor for many intestinal and chronic inflammatory diseases. Inflammatory bowel disease (IBD) and HIV infection are characterized by microbial translocation and systemic inflammation. Despite the clinical overlaps between HIV and IBD, significant differences exist such as the severity of gut damage and mechanisms of immune cell homeostasis. Studies have supported the role of metabolic activation of immune cells in promoting chronic inflammation in HIV and IBD. This inflammatory response persists in HIV+ persons even after long-term virologic suppression by antiretroviral therapy (ART). Here, we review gut dysfunction and microbiota changes during HIV infection and IBD, and discuss how this may induce metabolic reprogramming of monocytes, macrophages and T cells to impact disease outcomes. Drawing from parallels with IBD, we highlight how factors such as lipopolysaccharides, residual viral replication, and extracellular vesicles activate biochemical pathways that regulate immunometabolic processes essential for HIV persistence and non-AIDS metabolic comorbidities. This review highlights new mechanisms and support for the use of immunometabolic-based therapeutics towards HIV remission/cure, and treatment of metabolic diseases.

Regulation of Intestinal Epithelial Barrier and Immune Function by Activated T Cells

“…Chronic inflammation of the gastrointestinal tract often is associated with the loss of epithelial barrier integrity and resultant microbial translocation, as shown in many diseases that include IBD, irritable bowel syndrome, and human immunodeficiency virus infection. 16 , 19 , 20 Events that contribute to the pathology associated with intestinal permeability include the following: (1) direct damage to the epithelium, (2) dysbiosis of the luminal microbiome, and (3) local mucosal inflammation, with an important role for T-cell activation in disease progression and tissue damage. 21 , 22 Earlier reports showed that a single cytokine, such as TNF-α or interferon-γ (IFN-γ), can modulate the integrity of the intestinal barrier through alteration of TJ composition, owing to increased expression of incompatible claudin isoforms that exchange with the mobile fraction and lateral/cellular subpool.…”

Nelfinavir for COVID19: Summary of basic science data and initial clinical experience

“…GI involvement in COVID-19 is increasingly recognized. (17,18) The pathophysiology of COVID-19 GI tract involvement may be complex: in HIV enteropathy which has similar clinical presentation, GI tract continues to suffer from chronic inflammation and intestinal barrier dysfunction despite antiviral therapies (19,20). Prolonged antiviral therapies and additional therapies may be required to adequately address this problem.…”

Influence of HIV Infection and Antiretroviral Therapy on Bone Homeostasis

“…As an early event, the gut microbiome in HIV-infected individuals exhibits different compositions compared to uninfected individuals ( 57 , 58 ). Among them, the bacterial composition is altered on its diversity, genes, and functional capabilities, that are either pro-inflammatory or potentially pathogenic and whose abundance correlated with immune status ( 59 , 60 ). T-cell depletion is pronounced at the gut-associated lymphoid tissue (GALT) promptly after HIV infection, followed by an increase in the barrier permeability and microbial translocation with increased LPS levels ( 61 ).…”