Human Platelet Dysregulation by Antiretroviral Drugs and Cigarette Smoke in vitro

• Main Author: Loelius, Shannon G
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2019
• Subjects: Immunology
• ISBN: 9781085749916; 1085749916

In the past 30 years, a diagnosis of Human Immunodeficiency Virus (HIV) infection has changed from a death sentence to a chronic disease. This transformation is due to the advent of antiretroviral drugs (ARVs). While people living with HIV (PLWH) are living longer, they still have shorter lifespans compared to the uninfected population and are at higher risk for cardiovascular disease (CVD). The enigma is that PLWH successfully treated with ARVs, such that their viral load is undetectable, still experience chronic inflammation and increased CVD risk. Some epidemiological studies found that ARVs themselves may promote chronic inflammation and increase risk of CVD.Human platelets are key elements in inflammation, CVD risk, and thrombosis. PLWH have increased basal-levels of activated platelets, potentially contributing to increased CVD risk. Normally platelet activation is balanced to maintain hemostasis, with hypo-responsiveness resulting in bleeding and hyper-responsiveness resulting in inflammation.We hypothesized that ARVs could tip this balance toward inflammation, and thus, we investigated the effects of ARVs on platelet function. Screening ARVs on human platelets in vitro revealed that the antiretroviral drug ritonavir dysregulated platelet lipid mediator production, spreading, and aggregation. We next determined that ritonavir directly inhibited thromboxane synthase function, revealing a novel off-target effect of ritonavir. By performing a lipidomics analysis, we found that ritonavir dysregulated additional lipid mediator production.As cigarette smoking is a risk factor for CVD, and because PLWH tend to smoke more than the uninfected population, we examined the effects of ARVs combined with cigarette smoke on human platelet function in vitro. We found that cigarette smoke acts to exacerbate darunavir induced platelet dysregulation. Understanding the effects of combined environmental and ARV exposures on platelet function could lead to the development of therapeutics to prevent negative side effects, or in the development of ARVs with their effect on platelet function being considered.