The survival rates for HIV infected patients have dramatically increased over the last decade, leading to a growing population of HIV+ women who are postmenopausal and women who are in need of hormonal contraception, both, in effect, an altered hormonal state. Hormones play an important role in epithelial and endothelial cell function. Microbial translocation at mucosal epithelial sites increases systemic inflammation but its effect on endothelial surfaces is not known. Complications of HIV in the post-ART era are due to immune activation with resultant increase in age-related illnesses such as subclinical atherosclerosis. Thus, being postmenopausal or use of HC and HIV+ may serve to advance HIV progression and increase subclinical atherosclerosis in women. Hypothesis: Female sex hormones affect gut mucosal barrier function and microbial translocation which contributes to increased levels of systemic inflammation and augments subclinical atherosclerosis in postmenopausal HIV+ women and HIV+ women on hormonal contraception despite suppressive ART.
Aims and Methods: We will obtain peripheral blood and small intestinal biopsy samples from HIV+ premenopausal women and HIV+ premenopausal women on oral hormonal contraception (Groups 1 and 2) and HIV+ postmenopausal women and HIV+ postmenopausal women on hormone therapy (Groups 3 and4).
In Aim 1 we will examine the association between the altered sex hormonal status and impaired gut epithelial barrier integrity. We will measure markers of microbial translocation as well as levels of tight junction proteins. Comparison on Groups 1 and 2 will demonstrate the effects of Hormonal contraception (progesterone(Pg) based), Groups 1 and 3 will demonstrate the role of menopause (loss of estradiol) and Groups 3 and 4 will demonstrate the protective effects of estradiol (E2). We will also compare the microbial translocation in plasma of participants with that of their mucosal surface by phylogenetic analysis to demonstrate the role of the small intestinal mucosal integrity in microbial translocation.
In Aim 2 we will assess the effect of decreased gut mucosal integrity on systemic inflammation and cardiovascular risk.
In Aim 3 we will use in-vitro models to demonstrate that bacterial DNA stimulates endothelial inflammation and loss of integrity and identify the effects of E2 and Pg on endothelial inflammation. Responsiveness to FOA: We will demonstrate the relationship between inflammation, immune dysfunction and HIV related cardiovascular risk in women, elucidate hormone associated molecular mechanisms that play a role, and query the role of the gut microbiome in the development/augmentation of ART associated CVD. This study will further the independence of the junior PI towards a greater emphasis in HIV related HLB research. Innovation: The use of HC in HIV+ women is a highly debated topic at the WHO and other organizations. The effects of this chronic inflammation, in combination with altered hormonal status, on endothelial cells are highly relevant. Therefore, the proposed study is very timely and needed.
HIV+ women have a higher risk of inflammatory diseases due to systemic immune activation and inflammation. The cause is unknown. This study will identify the role of the sex hormones and their effects on the cardiovascular system in the development and maintenance of inflammation in the context of HIV infection. The mucosa is an important site of HIV pathogenesis and its impact on the cardiovascular system is truly exciting. The role of the gut as a gateway to improving general health in women is a novel concept and worthy of further investigation. (End of Abstract)
