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.

Keywords: HIV infection; adipose tissue; antiretroviral treatment; chronic immune activation; chronic inflammation; fat.

Figure 1

HIV-related alterations in AT. HIV itself and the viral proteins produced by infected cells induce fibrosis and alter adipogenesis and local immune functions. HIV proteins are secreted by infected cells within AT and can impact the nearby adipose stem cells (ASCs) and adipocytes. Dysfunctional ASCs present mitochondrial dysfunction, elevated levels of oxidative stress and a profibrotic phenotype. The proteins impede the ASCs’ ability to differentiate into adipocytes; this leads to dysfunctional adipocytes with low expression of adipogenic markers, lipid accumulation, and leptin and adiponectin secretion. HIV-protein-treated adipocytes also acquired a pro-inflammatory phenotype that is involved in local inflammation and immune dysfunction. Systemic factors (gut dysfunction, systemic chronic inflammation, and immune dysfunction) also contribute to AT dysfunction, with the induction of CD8 T cells, macrophages infiltration, and a shift towards a pro-inflammatory M1 macrophage profile.

Figure 2

Contribution of AT dysfunction to HIV-related low-grade inflammation. The exact degree of low-grade inflammation associated with chronic, controlled HIV infections remains subject to debate. The inflammation profile depends on the biomarkers studied and the clinical context of chronic HIV infection (including the time of ART initiation, and the severity of the primary phase of the infection). However, various triggers of inflammation are commonly reported to contribute to low-grade chronic inflammation: viral persistence, gut disruption, immunoregulatory defects, and non-HIV related comorbidities. Each of these main factors (shown in the inner circle) has several subfactors (shown in the outer circle). Fat alterations and the toxicity of ARVs also contribute.

Figure 3

ART-related fat alterations. ART controls HIV replication, improves systemic immune function, decreases chronic inflammation, promotes immune reconstitution and function, improves gut function and integrity, and decreases the viral load and viral protein concentration in the blood (A). However, it is not known whether ART decreases the number of infected T cells or the viral protein concentration within AT (B). Regarding conventional ART, the NRTIs stavudine and zidovudine, some PIs boosted by ritonavir, and the NNRTI efavirenz (EFV) induce alterations in AT such as fibrosis, altered adipogenesis, and local immune dysfunction. ART does improve immune function and expression levels of some adipogenic markers (e.g. PPARγ) in the AT, relative to treatment-naive HIV-infected patients. However, adipogenic marker expression is still lower than in non-infected people. ART induces mitochondria dysfunction and alters adipogenesis in both ASCs and adipocytes. ART-treated adipocytes present with oxidative stress and insulin resistance. Furthermore, some ARVs induce pro-inflammatory adipokine/cytokine secretion by adipocytes, ASCs and macrophages and CD8 T cells accumulation; this contributes to AT immune dysfunction and inflammation. It was recently reported that some INSTIs can be associated with fat and weight gain, adipogenesis, fibrosis, and adipocyte hypertrophy/dysfunction, with increased insulin resistance in vitro. INSTIs also induce collagen production, mitochondrial dysfunction, and oxidative stress in both ASCs and adipocytes, which might promote fibrosis. Nonetheless, the local impact of INSTIs on immune cells within the AT remains to be determined (C).

Figure 4

Inflammation changes in AT and are associated with comorbidities in ART-experienced, HIV-infected patients. AT alterations with VAT expansion, local and systemic inflammation, and gut dysfunction promote lipotoxicity in ART-experienced, HIV-infected people. Lipids accumulate in metabolic organs other than the AT, such as muscle, heart, blood vessels, liver, and pancreas. Lipotoxicity and inflammation might contribute to the development of atherogenic dyslipidemia, cardiovascular diseases, insulin resistance, diabetes, liver steatosis and NASH in the context of HIV infection and ART.