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.

Keywords: HIV cure; Immunometabolism, microbiome; Inflammation; Inflammatory bowel disease; Macrophage metabolism.

Fig. 1

Model showing potential inflammatory and immunometabolic consequences of gut barrier dysfunction in HIV infection. In HIV-negative persons the presence of Firmicutes in the gut enhances fermentation of dietary fiber to short chain fatty acids which have anti-inflammatory functions as well as promoting break down of glucose and fatty acid via oxidative metabolism (B). Damaged epithelial cells facilitate translocation of bacterial and fungal products across the intestinal lumen through the epithelial cells and into the blood stream. ROS and the inflammatory environment may cause low levels of HIV transcription and release of pro-glycolytic/inflammatory extracellular vesicles (EVs) by metabolically active CD4 T cells (B). The activation of monocytes/macrophages may increase the demand of glucose facilitated by increased Glucose Transporter 1 (Glut1) expression. High glycolytic metabolism by recruited monocytes and pro-inflammatory M1-like macrophages results in increased production of cytokines such as IL-6 and TNF which contribute to the chronic inflammation observed in HIV+ people. Figures designed using image stocks from nice-consultants.com.

Fig. 2

Key mechanisms of monocyte/macrophage activation and potential therapeutic interventions. Activation of monocytes and macrophages by may be mediated by interactions with TLRs. TLR4 engagement for example induces activation of the PI3K/Akt/mTOR axis and increases glutamine metabolism promoting pro-inflammatory cytokines and toxic nitric oxide production. Also indicated are potential points to therapeutically limit inflammation by repurposing currently available metabolic drugs used to treat cancers. Figures designed using image stocks from nice-consultants.com.