Immunometabolic Agitations Raises Risk of CVD in Patients with HIV

Faadiel Essop, PhD, BSc

Patients with HIV experience changes in their immune cells that may have implications for their risk of cardiovascular disease (CVD)—mostly increasing it.

A review of more than 80 studies was conducted by M. Faadiel Essop, PhD, BSc, of the Cardio-Metabolic Research Group as well as the Department of Physiological Sciences at Stellenbosch University in South Africa, and Eman Teer, PhD, also of Stellenbosch University, explored the developing role of “immunometabolism” in HIV-related dysregulation of the immune system and the onset of CVD.

“The mechanisms whereby activated immune cells become dysregulated and contribute to downstream effects such as immune activation, coagulation, and CVD onset in HIV-positive individuals remain poorly understood,” they wrote.

"Due to the successful roll-out of combination antiretroviral therapy during the last couple of decades, HIV is now increasingly being managed as a chronic condition," Essop told MD Magazine. "HIV-infected individuals are therefore exhibiting longer lifespans and evolving into an aging population. In parallel, such persons are displaying increased cardiovascular complications. This, in turn, will place a significant burden on health care costs, well-being, and economic prosperity, especially in developing countries."

"Although several factors are implicated in this process, our review article highlights the role of persistent immune activation as a significant driver of CVD development in HIV-infected individuals. Although most HIV-infected persons on anti-retroviral treatment do achieve viral suppression, this may not necessarily result in complete immunological recovery and it is an issue clinicians should be aware of when treating such patients," he added.

The use of combination antiretroviral therapy (cART) for patients with HIV, while lowering the viral load of many patients, has also resulted in a higher risk of heart attack, in addition to having an adverse impact on the cardiovascular system. This is especially alarming because having HIV can already lead to a higher risk of heart issues.

In their review, Essop and Teer found that consistent immune activation—a necessity and natural response in the treatment and management of condition—may result in pro-inflammatory and pro-oxidative processes during the early stages of the infection. Even low levels of the virus can lead to long-term inflammation and depletion of T cells.

The risk of CVD impacted by multiple factors, the review showed. All of these factors then contribute to a raised risk of CVD.

Once the infection occurs, T cells are activated, but low levels of viremia and lipopolysaccharide generation produced by cART result in persistent activation, and ultimately exhausting the T cells. This, in turn, leads to cytokine production capacity being reached, and pro-inflammatory response that increases coagulation.

Exhaustion of the T cells leads to lowered CD28 expression as well, which plays a large role in the peripheral tolerance. “The increased number of CD8+CD28— T cells can lead to subclinical CVD that are associated with higher morbidity and mortality,” Essop and Teer wrote.

In addition to coagulation increasing, the lipopolysaccharide generation leads to oxidative stress—a “vicious cycle” the authors wrote—that then further activates T cells and causes mitochondrial damage in T lymphocytes, leading to immune cell dysregulation. Compounded with that, the researchers found that increased glucose metabolism, also caused by persistent T cell activation, may then lead to alterations in lipids such as OX-LDL increases and lower LDL levels.

“All together, such changes increase the risk for CVD onset in HIV-positive individuals, despite the rollout of cART,” Essop and Teer noted.

"In particular, we believe markers of the immune and metabolic systems may provide excellent utility in this regard," Essop said. "Here the metabolic re-programming of immune cells that can contribute to the activation of coagulation pathways. The latter therefore provides an intriguing mechanism that can help explain how immune activation is actually linked to the onset of cardiovascular complications in HIV-positive individuals. Thus the re-programming of metabolic pathways in immune cells offer the potential for the design of novel therapeutic interventions to improve the overall health of HIV-positive individuals."

Also resulting from the increased activation of T cells is the depletion of CD4 counts, which have shown to be suggestive of increased risk for atherosclerosis.

“Despite changes in immune cell subsets defined in relation to plasma lipids and lipoprotein levels, there are currently no data available in terms of the role of immunometabolic changes in such patients,” Essop and Teer wrote. “We, therefore, advocate for additional studies to further examine our proposal that with low-level viremia and LPS-mediated changes there is a chronic shift to higher glucose metabolism in T lymphocytes.”

The review, “HIV and cardiovascular disease: role of immunometabolic perturbations,” was published in the journal Physiology.

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