Comparative Analysis of Thrombogenic Risk Across Menopausal Stages in Women with HIV

About This Grant

PROJECT SUMMARY Advancements in antiretroviral therapy (ART) have significantly increased the life expectancy of people with HIV (PWH). However, this extended longevity has brought about a heightened risk of cardiovascular disease (CVD). Notably, women with HIV (WWH) seem to face a disproportionately elevated risk of thrombotic adverse events, such as acute myocardial infarction (MI). Our group has reported significantly greater thrombogenicity in PWH using an ex vivo thrombosis model, with particularly marked findings among WWH, confirming the existence of sex-based differences in the underlying pathobiology. Although the precise mechanisms contributing to this greater increase in thrombogenic risk among WWH are not fully understood, certain key factors are emerging: (a) Generalized immune activation in HIV-1 infection strongly predicts the progression of both HIV and its comorbidities, including CVD. Women, in particular, exhibit a robust immune response and a higher risk of progressing to AIDS than men. Toll-like receptors (TLRs), crucial components of the innate immune system for their ability to recognize and respond to pathogens, including viruses, are influenced by estrogen levels and known to modulate platelet reactivity; (b) Platelets, the second most abundant blood cell type, play a crucial role in atherothrombosis and inflammation. Enhanced platelet reactivity is known to elevate the risk of CV events and has been reported in PWH. Additionally, platelets have been shown to express all 10 TLRs; (c) Age-related changes in sex-hormones affect the rates of CVD in women. Estrogens regulate vascular reactivity, blood pressure, endothelial function and also affect the immune system, and decrease in estrogen levels post menopause adversely affect traditional CV risk factors. Data suggest that WWH experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. Drawing from these key elements, we have formulated the hypothesis that HIV primes platelets increasing their responsiveness to TLR4 and TLR7 stimulation, and changes across the menopausal transition alter TLR-driven platelet activation and thrombogenicity in WWH through estrogen. The goal of this project is to define how HIV and reproductive aging interact to increase thrombotic risk in women with HIV, using functional thrombogenic assays integrated with exploratory molecular profiling to gain mechanistic insight. These initiatives are geared towards improving strategies for preventing and managing thrombotic events in this vulnerable population, ultimately enhancing patient outcomes and quality of life.