Leaky gut, clotting, and vasculopathy in SIV

In this issue of Blood, Pandrea et al provide a mechanistic link between SIV-associated microbial translocation and both thrombotic and cardiovascular disease in the pigtail macaque model.¹ 

The spectrum of disease affecting HIV-infected individuals has changed dramatically in the modern antiretroviral therapy (ART) era. While the incidence of opportunistic infections and malignancies has declined precipitously, HIV-infected individuals continue to have a shorter life expectancy than the general population and an increased risk of morbidities associated with aging including cardiovascular disease.²  While lifestyle factors (eg, smoking) and toxicities of antiretroviral drugs may contribute to cardiovascular risk in this setting, persistent HIV-associated immune activation has emerged as a major potential mediator in observational studies. Markers of immune activation, inflammation, and coagulation decline during ART-mediated viral suppression, but remain abnormally elevated and predict subsequent cardiovascular disease, thromboembolic events, and mortality in this setting.^3-6  For this reason, developing interventions to decrease persistent inflammation in treated HIV infection has emerged as a major focus of the HIV research agenda.

While the specific mechanisms driving the persistent inflammatory state and cardiovascular risk during treated HIV disease have not been definitively established, microbial translocation has emerged as a potentially important mechanism. Both HIV and pathogenic SIV infections result in impaired gut mucosal barrier function and abnormally high levels of microbial products including lipopolysaccharide (LPS) in peripheral blood, driving monocyte activation, which in turn predicts mortality in treated HIV disease.^7,8  LPS also results in tissue factor expression on monocytes, which activates the coagulation cascade, and has been associated with increased D-dimer levels in HIV-infected individuals, potentially contributing to the increased risk of cardiovascular and thromboembolic disease in this setting.⁹  However, these observational studies have not been able to prove that microbial translocation is a major cause of monocyte activation and coagulation in HIV disease. An SIV model that recapitulates HIV-associated thrombotic and cardiovascular disease would enable studies to define these causal relationships more definitively, to identify novel targets for interventions, and to test those interventions in preclinical studies.

The studies by Pandrea et al are a significant step forward in this regard. They demonstrate that pigtail macaques develop both atherosclerosis and thrombotic disease during chronic pathogenic SIV infection, mimicking the vascular pathology observed in HIV-infected individuals. Just as in HIV-infected individuals, vascular pathology in the pigtail macaque SIV model was associated with increases in systemic monocyte/macrophage activation and coagulation markers. Further suggesting a role of systemic immune activation in driving the vascular and thrombotic changes observed, none of this pathology was observed in SIV-infected African green monkeys and sooty mangabeys, which lack systemic immune activation in the chronic stage of the infection. Lastly, LPS administration to SIV-infected African green monkeys increased both monocyte/macrophage activation and D-dimer levels, providing the first experimental evidence that microbial translocation can cause coagulopathy in this setting.

Overall, the studies by Pandrea et al provide strong support for the hypothesis that HIV-associated immune activation—and specifically microbial translocation—contributes to cardiovascular risk, validating microbial translocation as a target for interventions. Indeed, several trials of interventions designed to decrease microbial translocation or its inflammatory consequences in the context of treated HIV infection are already in progress, but the existence of an animal model that recapitulates HIV-associated vascular and thrombotic disease will be invaluable for preclinical testing of future interventions.

The fact that D-dimer elevations are observed in both pathogenic SIV and HIV infections might also suggest a potential role for anticoagulant therapy. However, it remains unclear whether the hypercoagulability associated with pathogenic SIV and HIV infections is a cause of cardiovascular disease or simply a surrogate marker for monocyte activation, which may drive cardiovascular disease through atherosclerosis and plaque instability.¹⁰  Because D-dimer elevations predict subsequent thromboembolic disease in HIV-infected individuals,^3,6  it is plausible that the hypercoagulability observed in pathogenic SIV and HIV infections is clinically significant and potentially capable of contributing to the risk of myocardial infarction. This hypothesis could potentially be tested experimentally in the pigtail macaque model.

In summary, the studies by Pandrea et al are an excellent example of how animal models are being adapted to address the new clinical challenges facing the HIV-infected population and have the potential to accelerate the development of interventions to further reduce morbidity and mortality in this setting.