HIV and HIV therapy: What role does adipose tissue play?

Metabolic complications are a major challenge of HIV infection and antiretroviral therapy (ART). Many of these complications are mediated by adipose tissue. Current knowledge on this topic was presented at the virtual CROI 2020.

Optimization of HIV control and adipose tissue function as a two-track approach

Metabolic complications are a major challenge of HIV infection and antiretroviral therapy (ART). Many of these complications are mediated by adipose tissue. Jordan E. Lake, University of Texas Health Science Center, Houston (USA), presented the current knowledge on this topic at the virtual CROI in March 2020.

Many metabolic complications of HIV infection and antiretroviral therapy (ART) are mediated by the functions of adipose tissue. In her presentation, Lake justified the focus on fat in her presentation by the fact that the function of adipocytes affects almost every other organ system.

Among other things, adipocytes secrete inflammatory cytokines, which, when circulating in the bloodstream, contribute directly to metabolic disorders. Adipocytes themselves carry receptors for many hormones and inflammatory cytokines, which can change the function of the fat cell. Other organ systems can therefore also influence the function of the adipocytes.

The knowledge of the association of the functions of adipose tissue with the HI virus and with ART has improved significantly. The effects of ART can be seen in lipodystrophy, weight gain and subclinical changes in adipose tissue. The consequences are dysfunction of the mitochondria, lipid metabolism disorders, insulin resistance, adipose liver, and cardiovascular diseases.

"HIV and ART act on the adipose tissue and the adipose tissue acts on HIV," said the infectologist, adding that "optimizing HIV control and adipose tissue function is a two-track approach to reduce HIV-related morbidity and mortality".

Dysfunction of adipose tissue

Disorders in the adipose tissue are common with modern antiretroviral therapy. These include changes in distribution, quantity, and function. The adipose tissue dysfunction is favored by classical risk factors (such as overweight) as well as by the HI virus and by therapy-specific factors. The adipose tissue represents a unique reservoir for HI viruses.

Adipose tissue dysfunction is promoted by various factors of HIV and antiretroviral therapy such as:

The HI virus penetrates into the adipose tissue during an acute infection. In the simian immunodeficiency virus (SIV) model it could be shown that this leads to increased T cells and M1 macrophages migrating into the adipose tissue. Cell-associated HIV-DNA could be detected in test persons under ART, especially in tissue-resident CD4+ T cells. Resident T cells in adipose tissue express high levels of PD-1, which may facilitate HIV persistence.

The metabolic effects of the HIV virus, which are mainly mediated by inflammatory metabolic pathways, are manifested in untreated patients in catabolism, marasmus, elevated triglyceride and LDL cholesterol levels and lowered HDL cholesterol concentrations, mitochondrial dysfunction, inflammation of the adipose tissue, and insulin resistance. These effects may persist under ART, but they may differ depending on the patient’s sex.

Clinically, adipose tissue dysfunction is manifested in three overlapping syndromes, namely obesity, lipoatrophy & lipohypertrophy, and visceral adipose tissue accumulation.

Lipoatrophy is predominantly a legacy condition in individuals who have been treated with thymidine analogs. Obesity and overweight are widespread in HIV patients under ART. They are often accompanied by an increase in visceral fat tissue, which in turn is associated with various comorbidities, such as cardiovascular disease, non-alcoholic adipose liver, and type-2 diabetes mellitus.

Weight gain through antiretroviral therapy

In recent years, various studies have clearly shown that integrase inhibitors lead to greater weight gain than e.g. protease inhibitors or non-nucleoside reverse transcriptase inhibitors. This could be seen both in initial therapy and when switching to an integrase inhibitor. Weight gain with integrase inhibitors is more pronounced in women, blacks, the elderly and in patients with severe HIV infection. Among the various integrase inhibitors, dolutegravir appears to be the most potent in causing weight gain.

High-risk groups with particularly strong weight gain among integrase inhibitors are known, but the best therapeutic strategy or alternative is still unclear. Moreover, the benefits of treatment may outweigh the risk.

An open question is whether therapy-related weight gain has cardiometabolic implications.

Lake JE. Metabolic complications of HIV and its therapies. Virtual CROI 2020, Abstract 159.