September 12, 2017

Blocking the pathway to HIV-related cardiovascular risks

At a Glance

  • Researchers identified a pathway for the development of factors linked to cardiovascular events in people living with HIV.
  • An experimental drug blocked the pathway in monkeys.
  • More study is needed to find out whether such a drug could help reduce heart disease and stroke risk in people with HIV.
Micrograph of Giemsa-stained monocytes Immune system cells called monocytes, stained purple, release substances in HIV-infected people that may raise the risk of cardiovascular events.Dr. Graham Beards, CC BY-SA 3.0

More than 1 million Americans are living with HIV infection. HIV-fighting drugs help prevent the development of AIDS but don’t eliminate HIV from the body. Cardiovascular events, such as heart attacks and strokes, are a common complication of long-term HIV infection. People living with HIV are up to twice as likely as those without HIV to experience cardiovascular events, even when the virus is controlled.

The risk of cardiovascular events is increased by the presence of inflammation and abnormal blood clotting. Previous studies suggested that tissue factor (TF), a protein made by immune cells known as monocytes, may be involved in inflammation and abnormal blood clotting in HIV-infected people. People with long-term HIV infection have elevated levels of TF-producing monocytes.

A team of researchers led by Drs. Irini Sereti of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Ivona Pandrea of the University of Pittsburgh set out to further investigate the role of monocyte-derived TF in people with HIV. The study was also supported by NIH’s National Heart, Lung, and Blood Institute (NHLBI) and National Cancer Institute (NCI). Results were published on August 30, 2017, in Science Translational Medicine.

The team analyzed blood samples from people with HIV infection. They detected high levels of TF-producing monocytes in both people with controlled and uncontrolled HIV infections. They isolated TF-producing monocytes and showed that inflammatory signals in the blood of HIV-infected people triggered TF production in the monocytes. This process, in turn, led to the production of multiple substances that drive inflammation and blood clotting.

An experimental drug called Ixolaris is known to block the TF pathway. Ixolaris is an anticoagulant found in tick saliva. The scientists exposed blood samples from healthy people, HIV-infected-people, and monkeys with a virus related to HIV (simian immunodeficiency virus, or SIV) to Ixolaris. The drug blocked the TF pathway in all the samples.

The researchers then treated five SIV-infected monkeys with Ixolaris. Levels of substances associated with abnormal blood clotting and inflammation were lower in the treated monkeys than in untreated SIV-infected monkeys from previous studies.

These results suggest that blocking the TF pathway may slow the inflammation and clotting processes that place people with HIV at a higher risk of cardiovascular events. However, Ixolaris has not yet been tested in people, so its safety and ability to prevent inflammation, abnormal clotting, or cardiovascular events are unknown.

“The clinical link between HIV infection and heart attacks is clear and devastating,” says NIAID Director Dr. Anthony S. Fauci. “Understanding the cellular mechanism behind this connection is a crucial first step to providing comprehensive care for people living with HIV.”

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References: Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. Schechter ME, Andrade BB, He T, Richter GH, Tosh KW, Policicchio BB, Singh A, Raehtz KD, Sheikh V, Ma D, Brocca-Cofano E, Apetrei C, Tracy R, Ribeiro RM, Sher A, Francischetti IMB, Pandrea I, Sereti I. Sci Transl Med. 2017 Aug 30;9(405). pii: eaam5441. doi: 10.1126/scitranslmed.aam5441. PMID: 28855397.

Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), and National Cancer Institute (NCI).