Chronic HIV is associated with increased risk of pulmonary and cardiovascular complications. Despite use of antiretroviral therapy, rates of even rare vascular complications such as pulmonary hypertension occur upwards of 25 times that in HIV- individuals. The cause for such a high rate of vascular complications in HIV is unknown. Nitric oxide (NO) is a critically important signaling molecule that is produced by the vascular endothelium and acts as a vasodilator and regulator of cardiovascular health. Reduction of nitrate to nitrite and nitric oxide by commensal oral bacteria has recently been implicated in the maintenance of vascular function. The enterosalivary NO pathway is an important component of nitric oxide generation as nitrate is converted to nitrite by a series of bacterial enzymes in the mouth, which is then swallowed and either directly converted to NO or absorbed into the bloodstream where it exerts systemic NO-like effects. The enterosalivary NO pathway depends on viable populations of oral bacteria and helps regulate blood pressure and mitigate vascular injury. However, little is known about the specific bacterial populations involved or the contribution to systemic NO availability and vascular injury and disease. Our preliminary studies suggest that HIV+ individuals have a different profile of oral commensal bacteria (oral microbiome) than HIV- individuals that involves key nitrate reduction pathways. This study proposes the novel hypothesis that the accelerated cardio- and pulmonary vascular disease seen in HIV is due in part to changes in the oral microbiome that favor a disruption of the enterosalivary NO pathway, reduced NO availability, and chronic vascular injury. To test this hypothesis, the oral microbiome of an established cohort of 315 HIV+ and HIV- participants will be characterized using culture-independent sequencing techniques in banked oral wash samples. Expression of specific bacterial nitrate-reducing enzymes will be measured, and results correlated with available serological markers of vascular damage, echocardiographic testing, and radiographic measures of vascular injury. Results will directly inform future clinical enrollment of a prospective trial examining real-time nitrate metabolism, systemic NO distribution, and associated physiological effects. These investigations will offer the first stepsin understanding a novel pathway of HIV-associated vascular disease and inform development of targeted therapies. Additionally, this NRSA award will provide the candidate, a pulmonary medicine fellow, the opportunity for further training in pulmonary vascular medicine and for developing skills in HIV/AIDS and microbiome research. The candidate will acquire extensive training in basic and advanced laboratory techniques, biostatistics, and clinical study design through labwork, conferences, and a master's degree in clinical/translational research. The resources and experience of mentors Dr. Morris, an expert in HIV-related lung disease and the microbiome, and Dr. Gladwin, an expert in NO and pulmonary vascular disease, combined with the expansive array of resources available at the University of Pittsburgh, will support the candidate's successful development.
Pulmonary vascular and cardiovascular diseases remain a major source of morbidity and mortality in HIV-infected individuals in the current era of effective antiretroviral therapy. Reduction of nitrate to nitrite and nitric oxide by commensal oral bacteria has recently been implicated in the maintenance of vascular function. Normal populations of bacteria that live in the mouth are key in maintaining adequate levels of nitric oxide and thus important in vascular function, but these key bacteria may be altered in those with HIV and contribute to excess pulmonary vascular and cardiovascular risk. This proposal will determine changes in the oral microbiome in HIV, the impact of these changes on nitrate reduction pathways, and relationship to markers of vascular function.
|Koch, Carl D; Gladwin, Mark T; Freeman, Bruce A et al. (2017) Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med 105:48-67|