Reservoirs of HIV-infected cells that can’t be reached by antiretroviral therapy associated with an important marker of cardiovascular disease risk

By | November 16, 2020

The increased risk of cardiovascular disease observed in people with HIV taking effective antiretroviral therapy, even when they have an undetectable viral load, could be down to reservoirs of HIV-infected cells that cannot be reached by current treatments, according to research from San Francisco published in JAMA Network Open.

Researchers found that higher levels of cell-associated HIV RNA and DNA were associated with the formation of plaque in the carotid artery, an association that was independent of traditional risk factors for cardiovascular disease such as smoking, diabetes and high blood pressure.

“To our knowledge, our study is the first to demonstrate an association between the HIV reservoir and cardiovascular disease in HIV,” write the authors. “The independent association between cell-associated HIV RNA and DNA and the development of carotid plaque provides further evidence that HIV infection itself accelerates cardiovascular disease.”

Glossary

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

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ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection and cannot be eradicated with current treatments, but their size can be reduced by shortening the time between infection with HIV and starting HIV treatment.

Cardiovascular disease is one of the leading causes of serious illness and death among people with HIV. This cannot be entirely explained by the high prevalence of traditional risk factors among people living with HIV. Nor is the presence of a detectable HIV viral load a fully satisfactory explanation – increased rates of heart attack, stroke and other cardiovascular diseases are present even among people who are taking modern HIV treatment that suppress viral load below the limit of detection.

Dr Megan McLaughlin and her colleagues from the University of San Francisco hypothesised that higher cardiovascular disease risk could therefore related to the presence of reservoirs of HIV-infected cells that cannot be eradicated by current treatments.

To see if this was the case, they designed a study involving 152 people living with HIV, all of who were taking antiretrovirals and had an undetectable viral load. The study participants received care at San Francisco HIV clinics between 2003 and 2012.

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Hardening of the carotid artery was assessed at baseline and through follow-up by monitoring intima-media thickness (IMT) via ultrasound. This measures the thickness of the walls of the carotid arteries (which carry blood from the heart to the brain). This can help identify plaque (a build-up of fat, cholesterol and other substances) along the walls of the arteries, a recognised risk factor for cardiovascular disease.

Levels of cell-associated RNA and DNA were checked using blood samples obtained from each participant and subsequently frozen.

Information was gathered on demographics, the presence of risk factors for cardiovascular disease and markers of systemic inflammation. All these were taken into account by Dr McLaughlin and her co-investigators in their analyses to see if HIV persistence translated into hardening of the carotid artery.

Most of the participants were White (70%) and male (92%). The median age was 47 years. The average time since HIV diagnosis was 13 years and participants had been taking antiretrovirals for a median duration of five years. Traditional risk factors for cardiovascular disease were common: 60% were current/previous smokers, 30% had high blood pressure, and 22% had a family history of premature cardiovascular disease.

The mean period of follow-up was a little over four years. Mean carotid intima-media thickness at baseline was 1.20cm, increasing to 1.23cm at the end of follow-up. Carotid artery plaque was detected at baseline in 57% of individuals, which thickened in almost all of these individuals (95%) during follow-up. New plaque was detected in a third of those who did not have plaque at baseline.

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Statistically significant risk factors for carotid artery plaque at baseline included older age, smoking, hypertension requiring treatment, higher LDL or ‘bad’ cholesterol, and elevated IL-6 (a marker of inflammation). Neither cell-associated HIV DNA nor RNA were shown to be risk factors. But the authors believe that the very strong associations with traditional risk factors made it difficult to unmask the role of HIV reservoirs.

“Decreasing the HIV reservoir size might have an effect on reducing atherosclerosis and cardiovascular disease risk.”

During follow-up, there was an association between hardening of the carotid artery and levels of both HIV RNA (p = 0.047) and HIV DNA (p = 0.042). But these associations ceased to be statistically significant when the authors took into account other risk factors.

However, there was a connection between the formation of new carotid artery plaque and levels of cell-associated HIV RNA and HIV DNA that was highly statistically significant, even after taking into account other risk factors (p = 0.008 and p = 0.02, respectively).

Black race was also identified as a risk factor for the formation of new plaques (p = 0.049).

“Our results suggest that decreasing the HIV reservoir size through strategies such as early ART might have an effect on reducing atherosclerosis [hardening of the arteries] and cardiovascular disease risk in this population, although further research is required,” write the researchers. “Strategies targeting the size of the reservoir as a means to a cure or control of HIV may help reduce the burden of comorbid disease in people living with HIV. Multiple strategies aimed at reservoir reduction are now being pursued in the clinic.”

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