Adipose Tissue in HIV Infection

Abstract

HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-γ and other regulatory gene expression, and increased pro-inflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently-infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage.

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

“…The adipose toxicity of the first generation of ARVs (notably in in vitro assays) has been extensively described (Koethe, 2017). Nevertheless, the pharmacokinetics and intracellular metabolism of ARVs in adipocytes have not been extensively characterized.…”

“…Special focuses have been obviously given to the metabolic consequences of fat tissue infection that will be only briefly discussed in this review [see the excellent review on the subject (Desruisseaux et al, 2007;Koethe, 2017;Couturier and Lewis, 2018;Godfrey et al, 2019)]. Works are still ongoing notably to decipher the respective impact of the local viral infection and antiretroviral treatment.…”

HIV Persistence in Adipose Tissue Reservoirs

“…Murine models would later demonstrate migration of immune cells into adipose tissue to become major regulators of adipocyte function and metabolism, and studies of healthy and diseased humans further showed significant accumulation of immune cells [24–27]. Additionally, virion-free circulating HIV proteins such as vpr, nef, and tat were shown to mediate detrimental effects on adipose tissue health and systemic metabolism [28–35]. In light of findings such as these and the need to better understand HIV tissue reservoirs and latency, the question of HIV persistence in adipose tissue is of high significance.…”

Adverse effects of chronic treatment with the Main subclasses of highly active antiretroviral therapy: a systematic review

“…The use of HAART has led to substantial improvements in the suppression of HIV replication and in the life expectancy of the infected population. However, the combination of drugs used in HAART favours the appearance and development of metabolic changes which can lead to the occurrence of the lipodystrophy syndrome .…”

“…HIV proteins persist in the circulation despite suppression of plasma viraemia, and can impair adipocyte maturation, reduce mRNA expression of key regulatory proteins, and alter cytokine signalling profiles. In addition, use of antiretroviral drugs can lead to visceral fat accumulation and a combined phenotype of insulin resistance and dyslipidaemia .…”