Obesity and Fat Metabolism in Human Immunodeficiency Virus-Infected Individuals: Immunopathogenic Mechanisms and Clinical Implications

Abstract

Metabolic complications relating to complex effects of viral and immune-mediated mechanisms are now a focus of clinical care among persons living with human immunodeficiency virus (PLHIV), and obesity is emerging as a critical problem. To address knowledge gaps, the US National Institutes of Health sponsored a symposium in May 2018 entitled "Obesity and Fat Metabolism in HIV-infected Individuals." Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among PLHIV. Fibrotic subcutaneous adipose tissue is metabolically dysfunctional and loses its capacity to expand, leading to fat redistribution, including visceral obesity and ectopic fat accumulation, promoting insulin resistance. Viral proteins, including viral protein R and negative regulatory factor, have effects on adipogenic pathways and cellular metabolism in resident macrophages and T cells. HIV also affects immune cell trafficking into the adipose compartments, with effects on adipogenesis, lipolysis, and ectopic fat accumulation. Key cellular metabolic functions are likely to be affected in PLHIV by gut-derived cytokines and altered microbiota. There are limited strategies to reduce obesity specifically in PLHIV. Enhancing our understanding of critical pathogenic mechanisms will enable the development of novel therapeutics that may normalize adipose tissue function and distribution, reduce inflammation, and improve insulin sensitivity in PLHIV.

Keywords: HIV; inflammation; metabolism; obesity; viral proteins.

Figure 1.

Spectrum of body composition changes past, present, and future in human immunodeficiency virus (HIV). Fat dysfunction in HIV related to loss of subcutaneous adipose tissue (SAT) or lipoatrophy, gain of visceral adipose tissue (VAT) or lipohypertrophy, and gain of SAT and VAT in obesity.

Figure 2.

Human immunodeficiency virus (HIV)/viral protein effects on adipose-specific Dicer, and implications of Dicer expression to lipodystrophy in preclinical and human models. A, Potential mechanism of HIV and viral accessory protein–mediated suppression of Dicer leading to microRNA dysregulation and fat dysfunction in brown adipose tissue and the epididymal and inguinal adipose depots [21]. B, Adipose-specific knockout mice demonstrate a lipodystrophy phenotype compared to control mice. Arrow depicts dorsocervical fullness and arrowheads depict loss of subcutaneous adipose tissue [22]; C, Significant reduction in Dicer expression in abdominal subcutaneous adipose tissue, with a stepwise decrease in expression demonstrated to be highest among non-HIV-infected individuals and most reduced among HIV-infected individuals with lipodystrophy [23]. Figures adapted and used with permission [21–23]. Abbreviations: AU, arbitrary units; BAT, brown adipose tissue; Epi, epididymal; HIV, human immunodeficiency virus; Ing, inguinal; KO, knockout; Lipo, lipodystrophy; mRNA, messenger RNA; TBP, TATA-box binding protein; Vpr, viral protein R.

Figure 3.

Model of how immune cell metabolic programming in human immunodeficiency virus (HIV) infection drives inflammation and may promote comorbidities. Inactivated T cells and monocytes utilize oxidative phosphorylation to generate adenosine triphosphate from fatty acids and limited glucose. During activation, cells undergo metabolic reprogramming toward a proinflammatory glycolytic profile by increasing surface glucose transporter 1 to increase glucose uptake. Metabolically activated monocytes may be recruited to arterial endothelium where they bind and migrate to the intima, differentiate into macrophages, and perpetuate atherosclerosis. Likewise, activated peripheral immune cells may be recruited to adipose tissue to orchestrate an inflammatory environment. Abbreviations: Glut 1, glucose transporter 1; IFN-γ, interferon gamma; IL-6, interleukin 6; OXPHOS, oxidative phosphorylation; TNF, tumor necrosis factor.

Figure 4.

A, Gut and white adipose tissue homeostasis in human immunodeficiency virus (HIV)–uninfected lean individuals. Commensal bacteria and microbial products such as lipopolysaccharide (LPS) are restricted to the gut lumen by an intact mucosal barrier. Short-chain fatty acids (SCFAs) produced by “good” bacteria, eg, firmicutes, from the metabolism of complex fibers produce SCFAs such as butyrate, which maintain gut integrity and production of anti-inflammatory cytokines by immune cells within the lamina propria. SCFAs also regulate GPR43 on adipocytes to suppress lipid accumulation. In lean white adipose tissue, Th2 lymphocyte and M2 macrophages predominate, and anti-inflammatory cytokines and insulin-sensitizing adipokines are released. B, Model of gut and white adipose tissue homeostasis in obese people living with HIV (PLHIV). HIV causes a breach of intestinal epithelial barrier due to loss of tight junctions. Translocation of commensal bacteria and bacterial products including LPS and metabolites from the gut lumen into the lamina propria ensues. HIV infection depletes lamina propria CD4⁺ T cells and, combined with a compromised gut barrier, induces potent proinflammatory gut response. Translocation of microbial products into white adipose tissue and peripheral blood causes systemic and white adipose inflammation that may promote or exacerbate obesity and creates a vicious cycle. In PLHIV, a disordered gut microbiome, characterized by reduced bacterial diversity and a shift from Firmicutes dominating phyla to pathobionts such as Proteobacteria and Bacteroidetes has been described. SCFAs such as propionate and acetate are produced, which have important immunological activity only now being elucidated. Metabolically activated and inflammatory immune cells within obese white adipose tissue secrete chemokines and proinflammatory cytokines, and enlarged adipocytes secrete free fatty acids and adipokines that induce insulin resistance. Activated resident CD4⁺ T cells and macrophages within adipose tissues are also targets and reservoirs for HIV. Abbreviations: FA, fatty acid; FFA, free fatty acid; HIV, human immunodeficiency virus; IL, interleukin; MCP-1, Monocyte chemoattractant protein 1; SCFA, short-chain fatty acid; TNF, tumor necrosis factor.

Figure 5.

Selected interventions for managing obesity. Asterisks (*) indicate those strategies that are literature-based for treatment of human immunodeficiency virus (HIV) obesity as well as obesity without HIV. Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; DASH, Dietary Approaches to Stop Hypertension; DPP-4, Dipeptidyl peptidase-4; GLP-1, Glucagon-like peptide-1; PPAR-γ, peroxisome proliferator–activated receptor gamma.