Changes in Enteric Microbiota and Inflammation with HIV PrEP

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Although HIV remains a major global health problem, strategies such as Pre-Exposure Prophylaxis (PrEP) can reduce the incidence of new infections. However, the antiretrovirals used for HIV prevention have been associated with increased enteric inflammation in individuals using them. We hypothesize that their broad activity affects both the viral and bacterial communities of the gut, causing local inflammation which may cause epithelial dysfunction and increase microbial translocation and systemic inflammation. We propose a series of metagenomic experiments to characterize the inflammatory contributions of intestinal viruses and bacteria and their changes with PrEP. For this novel research, we must first enroll a cohort of participants starting HIV PrEP and a similar group of control participants not using PrEP. We will collect blood and stool samples at baseline and after three months. First, we will characterize the virome fromstool specimens using metagenomic sequencing of filtered viral particles and compare the changes of within- and between- individual diversity in the participants on PrEP and those in the control group (aim 1). Next, we will use metagenomic sequencing to characterize stool bacterial populations, including prophages (aim 2). We will computationally predict bacterial targets of bacteriophages, then culture the identified virus-bacterial pairs from participant specimens. Using these cultures, we will validate the predicted interactions and assess the ability of PrEP to disrupt them. Finally, we will measure inflammatory markers in stool and blood and use the viral and bacterial abundances to identify which organisms are most strongly associated with inflammation (aim 3). These experiments will identify viruses and bacteria which interact with each other and with PrEP and define their impact on host inflammation. Dr. Maust’s career development plan builds on his background in computational biology, and lab expertise in analyzing bacterial communities by marker gene sequencing and adds training in metagenomic sequencing, biostatistical techniques, and methods for viral and bacterial culture. This K08 award is a well-structured way for him to make maximal use of UW and Seattle Children’s extensive scientific resources to achieve independence as a physician scientist, advancing his career goal to understand microbial interactions as they impact host immunity to guide therapeutic interventions.