The widespread availability of potent anti-HIV therapy has prolonged the survival of HIV-positive people, particularly those who live in high-income countries and who are engaged in their care and treatment. However, anti-HIV therapy does not cure HIV infection and increased survival is accompanied by other problems, most notably an apparent acceleration of the aging process that affects many organ-systems.
How might prolonged HIV infection accelerate the aging process? Researchers are not certain but have begun to study the interaction between HIV and aging. One possible way prolonged HIV infection might cause damage to the body is through chronic immune activation. Shortly after encountering HIV, the immune system goes into an activated state as it tries to contain this infection. Unfortunately, HIV can evade the body's defenses, and once infection becomes chronic a lifelong fight between the immune system and HIV ensues. This prolonged struggle between the immune system and HIV ensures that the cells of the immune system are often in an activated state. Furthermore, the heart and blood vessels are particularly vulnerable to damage arising from immune activation.
Therapy for HIV greatly suppresses levels of this virus. With reduced levels of HIV, thed the immune system does attempt to turn off its activation . However, this is not completely successful. The immune system communicates with and can affect other organ-systems. Indeed, some of the immune system's cells even take up residence in organ-systems. There, they release chemical messengers that can inflame tissue; over time, this inflammation can lead to damage.
Researchers at Harvard University have been studying the impact of HIV on the blood vessels of HIV-positive men. Their findings suggest that in relatively young, symptom-free men, HIV infection can cause a narrowing of the arteries, increasing the risk for a heart attack.
Researchers recruited 110 men who were divided into two groups as follows:
The data from HIV-negative men were used for purposes of comparison and our report will focus on HIV-positive men.
All men in the study were symptom-free and at the time of recruitment were not known to have cardiovascular disease (CVD).
Participants were interviewed, examined and had CAT scans of their heart performed. In addition, a cardiologist performed coronary angiography -- a procedure to assess blood flow in the vessels that supply oxygen-rich blood to the heart.
The average profile of HIV-positive participants was as follows:
Of the four men who were not taking anti-HIV therapy, their CD4+ counts were about 800 cells and viral load just over 1,000 copies.
Analysis of information gathered from blood samples, physical examinations and interviews found that factors such as age, race, diet and weight were similar between the two groups. Results from most blood tests regarding cholesterol and sugar were also broadly similar. Based on these results, the men would have been considered at low risk (about 5%) for having a heart attack in the next 10 years.
Although the results of traditional assessments of CVD seemed reassuring, when researchers analysed the findings from CAT scans and angiography they found that nearly 60% of the HIV-positive men had sticky deposits on the walls of their arteries. These deposits are called plaque and are made up of cholesterol, debris and sometimes calcium; they also can contain cells of the immune system that are attracted to plaque because of inflammation. Large plaques can clog arteries and choke the flow of blood and oxygen to the heart, which can lead to a heart attack. Sometimes plaques can rupture and trigger the formation of blood clots that block the flow of blood, leading to heart attacks and, if the clots reach the brain, stroke. In contrast, among the HIV-negative men, only 34% had plaques in their arteries. This difference was statistically significant.
The researchers also found that in about 7% of HIV-positive men there was a great deal of blockage in the arteries that supply oxygen and nutrients to the heart -- the coronary arteries. In 7% of HIV-positive men, at least 70% of blood was blocked from flowing through to the heart. This blockage increased their 10-year risk of a heart attack from 5% to 12%. In contrast, among HIV-negative men with a significant narrowing of the arteries, their 10-year risk of a heart attack was about 4% -- a significant difference.
In five HIV-positive men who had significantly narrowed arteries, the researchers informed their family doctors and asked them to refer the men to a cardiologist. Here is what happened:
The remaining three men were evaluated by cardiologists who conducted further testing, which confirmed that they had severely narrowed arteries. One of the three underwent coronary bypass surgery; another had a stent placed inside his artery to keep it open. In the case of the fifth man, doctors tried to implant a stent but failed. They also prescribed cholesterol-lowering medicines but the man was unable to tolerate them. Two years later, investigation revealed that his arteries had narrowed even more and so he received bypass surgery. All three people are "doing well," according to the research team.
The study team found that HIV-positive men with plaque in their arteries were likely to have the following features:
Although some observational studies have linked exposure to anti-HIV drugs to an increased risk for CVD, the Harvard study did not. However, the researchers did find that men who had high levels of antibodies to a virus called CMV (cytomegalovirus) were more likely to have evidence of heart disease.
Taking many factors into account -- including age, use of protease inhibitors, cholesterol levels, viral load, CD4+ cell count -- the researchers found that the longer a person had been HIV positive, the greater the likelihood that they had extensive and thick deposits of plaque.
Calcium can sometimes be deposited in plaque. Some studies of plaque have focused only on finding calcium-containing plaque and linking these to an increased risk for CVD. These studies produce a calcium score to indicate the level of calcium in arteries. However, plaques may be present without detectable calcium deposits. The Harvard team noted that in their study "a significant proportion of patients with coronary atherosclerosis would have been missed if calcium score was used as the sole [way to assess] coronary atherosclerosis."
The findings from the Harvard study suggest that there is a link between HIV infection and narrowed arteries that is independent of traditional CVD risk factors. This link appears to be related to the length of time a person has been HIV positive. HIV plays a role in CVD, perhaps by triggering or intensifying inflammation.
That the CD4/CD8 ratio was linked to CVD suggests that the immune system may also play a role in this problem. Another clue comes from the finding that higher levels of the immune system chemical messenger MCP-1 were found in men at high risk for CVD. MCP-1 attracts a group of cells called monocytes. Monocytes, and their mature form called macrophages, are found throughout the body. Previous research has found that MCP-1 is an important signal that attracts monocytes to plaques in arteries. HIV-infected cells release proteins that also stimulate the release of MCP-1. And other researchers have found that MCP-1 is linked to an increased risk of CVD in both HIV-negative and HIV-positive people.
Cytomegalovirus, or CMV, is a member of the herpes family of viruses. In immune-suppressed people with low CD4+ counts, CMV infection can cause ulcers and damage the light-sensitive portion of the eye, leading to blindness. Some researchers have a theory that CMV infection is linked to an increased risk for CVD. Data for this theory arises from research in mice that shows that CMV infection can raise blood pressure and perhaps cause other complications. Studies of large numbers of people have found an association between having CMV infection and CVD. However, more research needs to be done in people to understand the possible role played by CMV as a risk factor for CVD in HIV-positive people.
The Harvard study focused only on men. Additional studies are needed to monitor CVD health in both HIV-positive men and women over time to see if the present study's findings change. Important questions such as the following need to be answered: