Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

Abstract

White adipose tissue (AT) contributes significantly to inflammation – especially in the context of obesity. Several of AT’s intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.

Distinct Plasma Concentrations of Acyl-CoA-Binding Protein (ACBP) in HIV Progressors and Elite Controllers

“…Moreover, ACBP levels were only analyzed in plasma samples. The tissue expression of ACBP, notably in the liver and adipose tissue, should be compared in ECs vs. ART-naïve and ART-treated PLWH [ 42 ]. The comparatively low ACBP plasma levels of ECs could reflect a reduced secretion of ACBP, as well as a lower expression of intracellular ACBP.…”

Adipose Tissue Extracellular Matrix Remodeling in Response to Dietary Patterns and Exercise: Molecular Landscape, Mechanistic Insights, and Therapeutic Approaches

“…Excessive ECM production in adipose tissue (i.e., fibrosis) is a characteristic of the unhealthy phenotype found in non-alcoholic steatohepatitis development, inflammatory conditions, insulin resistance, and breast cancer [10][11][12][13][14]. Recent evidence indicated that fibrosis is strongly associated with obesity, metabolic dysfunction, and difficulty in weight loss, suggesting that the ECM microenvironment may increase disease progression [6,9,15]. Presently, there is great concern in investigating approaches to attenuate the harmful effects of ECM enlargement.…”

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy

“…Both HIV infection and ART modify the adipose tissue composition, distribution, and function [12,17]. The virus itself targets adipose tissue directly by infecting adipose tissue-resident cells (notably CD4 + T cells) and indirectly via viral protein release, activation of inflammation, and the immune system and gut disruption [18]. Furthermore, in obese PLHIV, adipose dysfunction is boosted by inflammation, which in turn is an outcome of excess adipose and obesity-induced metabolic disturbances.…”