Accelerated ageing of the immune system linked to heart disease risk in women with HIV

Accelerated ageing of the immune system, caused by chronic HIV infection, was strongly associated with harmful changes in the carotid artery that may lead to long-term cardiovascular disease in women with HIV, US researchers report in an article published in advance online by the Journal of Infectious Diseases.

People with HIV infection appear to have an elevated risk of cardiovascular disease such as heart attack and stroke. People with HIV also have a high frequency of subclinical signs of progressive cardiovascular disease, or atherosclerosis, such as greater deposition of cholesterol and other debris on the walls of arteries (plaques), and thickening of the walls of the carotid artery.

In part these changes are due to lifestyle factors such as smoking, which is more common in people with HIV, and raised cholesterol levels caused by some antiretroviral drugs.

However there is growing concern that even in the absence of multiple risk factors, long-term infection with HIV may directly increase the risk of heart disease by promoting a permanent inflammatory state. Chronic viral infections can also cause accelerated ageing of the immune system, which may damage blood vessels in ways that promote the development of heart disease.

Dr Robert Kaplan of Einstein College of Medicine, New York, led a study to investigate the effect of accelerated ageing of the immune system on the cardiovascular health of women with HIV infection.

Ageing of the immune system (immunosenescence) is characterised by a decline in the number of new naïve T cells manufactured, a loss of memory T cells programmed to respond to specific infections, less aggressive proliferation of T cells in response to infections and higher levels of some inflammatory cytokines. All these defects explain why older people may be prone to more infections, and to suffer more ill health when they do acquire an infection.

These traits of an ageing immune system are usually seen in the elderly, and have been linked to heart disease. This study set out to determine if immunosenescence can also be found in younger people with HIV infection, and the extent to which it predicted cardiovascular disease.

The study compared measures of carotid artery disease and T-cell activation and immunosenescence in 115 HIV-infected women and 43 HIV negative women matched by age and ethnicity. All were participants in the Women’s Interagency HIV Study, a prospective study that included carotid artery ultrasound scans in its investigations.

The investigators measured  T cell activation by looking at levels of co-expression of CD38 and HLA-DR markers on CD+ and CD8+ T cells, and senescence by looking at the absence of CD28 and presence of CD57 markers.

They found significantly higher frequencies of activated CD4+ and CD8+ T cells, and of senescent CD8+ T cells, in HIV-positive women. Activation was lower, but not absent, in women on fully suppressive antiretroviral therapy, indicating that even very low levels of HIV continue to cause immune dysregulation.

The level of activation in women with HIV was associated with the extent of carotid artery lesions, after controlling for age, CD4 count, viral load and antiretroviral therapy. Activation in women without HIV was lower and not associated with carotid artery lesions, suggesting either an effect of HIV or concurrent pathogens such as CMV or hepatitis C on the vascular wall, or the existence of a threshold of immune activation that is necessary before it affects the vascular wall.

A higher level of CD8+ T cell senescence was significantly associated with carotid artery lesions in HIV-positive women, but not in HIV-negative women (p=0.009). This was not reversed by antiretroviral therapy.

The study is limited by its cross-sectional design which relied on measurements and blood samples taken at one visit in women, and prospective data are needed to further understand the links between immune activation, immunosenescence and cardiovascular disease in people with HIV.

In an accompanying commentary Virginia Triant and Steven Grinspoon of Massachusetts General Hospital say that long-term follow-up is needed to better understand the association seen in this study, with further investigations required to see whether the same phenomenon is found in men.

They also note that if the association holds in future studies, attempts to treat immune senescence through immunosuppressive drugs, cytokine inhibitors or teleomere-based therapies “will need to be balanced against potential negative immunological effects. Indeed this balance may be difficult to achieve.”

Kaplan RC et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis, advance online publication, January 10^th, 2011. Click here for a link to the free article.

Trant VA, Grinspoon SK. Immune dysregulation and vascular risk in HIV-infected patients: implications for clinical care. J Infect Dis , advance online publication, January 10^th, 2010, Click here for free access to an extract from this article.