(WASHINGTON) – Researchers have identified microbial translocation, the leaking of bacteria from the intestine into the bloodstream that causes chronic inflammation, as a critical factor in the development of cardiovascular disease (CVD) in patients with HIV. Study results were recently published online in Blood, the Journal of the American Society of Hematology (ASH).
Thanks to the success of highly active antiretroviral drug therapy (HAART), it has become increasingly possible for patients with HIV to live longer, healthier lives. However, individuals with HIV are twice as likely as those without the virus to develop CVD, which has become one of the leading causes of death in HIV-infected people. Previous research suggests that the heightened risk and increased incidence of CVD in HIV patients may be attributed in part to metabolic side effects of long-term HAART treatment, such as abnormal fat and sugar levels in the blood; however, the relationship between HIV infection, antiretroviral therapy, and CVD risk has remained unclear.
“Until now, the relationship between HIV and CVD has remained largely a mystery, and has unfortunately prevented us from developing interventions that may reduce CVD mortality in patients with HIV,” said Ivona Pandrea, MD, PhD, Associate Professor of Pathology at the University of Pittsburgh School of Medicine. “CVD is difficult to study in humans because of multiple risk factors that can contribute to its development, including obesity, tobacco use, age, race, and family history of heart disease. Thus, an efficient animal model is needed in order to study the mechanisms of HIV-related CVD.”
To better understand the HIV-CVD connection, Dr. Pandrea and colleagues embarked on a study examining CVD incidence and development in nonhuman primates infected with simian immunodeficiency virus (SIV), a monkey virus similar but not identical to HIV. Several types of primates are commonly used as animal models for HIV/AIDS research because of their similar genetic and physiological characteristics with humans. Some species are useful as they are able to emulate the process of HIV infection and disease progression to AIDS (pigtailed macaques and rhesus macaques), while others are subject to intense research to determine why they do not develop AIDS despite a high incidence of SIV infection (African green monkeys and sooty mangabeys).
Pandrea and collaborators first set out to define which primate would serve as the best model to study CVD development. They investigated the four different species infected with SIV and found that the pigtail macaque was the best model because of an increased propensity for blood clots associated with SIV infection, a high incidence of CVD, and abnormally high levels of immune system activation that causes chronic inflammation.
Using the newly identified pigtail macaque disease model, the researchers then sought to investigate the mechanisms of CVD. Although previous research had pointed to HAART as the major factor that increases the risk of CVD, Pandrea and colleagues wanted to determine whether HIV infection in itself may also play a role in CVD development. After infecting the African green monkeys and pigtail macaques with the same virus strain without administering HAART antiretroviral treatment, only the pigtail macaque had evidence of CVD, demonstrating that CVD can occur in the absence of HAART.
“The demonstration that CVD can occur in the absence of antiretroviral therapy was very important to us because it not only shows that HIV infection itself does induce CVD, it also underscores the utility of nonhuman primates in HIV/AIDS research,” said Dr. Pandrea, also a member of the University of Pittsburgh Center for Vaccine Research. “These kinds of results are difficult to obtain in humans because patients cannot be left untreated.”
These findings also proved that the virus alone does not play the major role in CVD development since both species were identically infected yet only the pigtail macaque with progressive infection (SIV infection progressing to simian AIDS) developed CVD. This observation led the researchers to hypothesize that there are other individual risk factors beyond the virus itself driving the development of CVD in these primates.
In order to identify what other individual factors could play a role in the development of CVD, the researchers compared rhesus and pigtail macaques with progressive infection to African green monkeys and sooty mangabeys with nonprogresive infection and found that only the species with progressive SIV with high levels of immune system activation and microbial translocation, a leaking of bacteria from the intestine into the bloodstream, developed CVD. The researchers then hypothesized that microbial translocation induces immune activation and inflammation, which drive CVD development.
After administering a microbial toxin lipopolysaccharide, a compound meant to mimic microbial translocation, to the African green monkeys with nonprogressive SIV infection, the researchers observed a significant increase in the SIV viral load and in immune activation and inflammation in these primates. Researchers also observed increased levels of the coagulation markers d-Dimer and thrombin-anti-thrombin (TAT) complex, found when the body creates excessive blood clots that are known to increase the risk of CVD. These results suggest that microbial translocation is a driver of CVD in HIV-positive patients.
“The results of our study demonstrate that microbial translocation, which induces immune activation and inflammation, plays a major role in the development of cardiovascular disease,” said Dr. Pandrea. “Our next step is to conduct a trial to attempt to decrease microbial translocation in pigtailed macaques and then to transfer that knowledge to HIV patients to potentially reduce cardiovascular disease morbidities.”
Reporters who wish to receive a copy of the study or arrange an interview with the authors may contact Claire Gwayi-Chore at 202-776-0544 or firstname.lastname@example.org.
The American Society of Hematology is the world’s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood, the most cited peer-reviewed publication in the field, which is available weekly in print and online.