These 12-month projects cover a range of topics that are high priorities for NIH’s Office of AIDS Research. The project leaders will collaborate closely with multiple core directors and utilize CFAR core services to complete these high impact projects.
Adolescent MSM’s perspectives on novel biomedical HIV prevention approaches
Adolescent men who have sex with men (AMSM) in the US are disproportionately affected by HIV and accounted for 63.4% of new infections among adolescents from 2010-2014. Daily oral pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention method FDA approved for adults that has great potential to curb infection rates among AMSM, and approval of daily oral PrEP for adolescents is on the horizon. However, many AMSM faced challenges with adherence to daily oral PrEP which impacted its effectiveness, and individual and structural barriers may impact uptake of daily PrEP. This project seeks to conduct an online, qualitative study to shed light on AMSM’s perspectives on event-driven, injectable, and implantable PrEP.
Results will inform whether and how changes may need to be made to the development and implementation of novel HIV prevention products to increase AMSM interest, uptake, and adherence when these products are approved for adolescent use.
Sex Differences in HIV-Related Gut Dysbiosis and Myocardial Dysfunction
This work will define how sex-specific differences in gut microbiota relate to cardiac disease for men and women living with human immunodeficiency virus (HIV). We propose to collect stool specimens and perform metagenomics analyses of gut microbiota for participants in an American Heart Association (AHA)-funded study MI HEART (Myocardial Imaging in HIV to Evaluate Arterial and Related Triggers of Dysfunction) evaluating potential mechanisms implicated in coronary and myocardial dysfunction for men and women with HIV as well as uninfected controls.
The MI HEART investigators already plan to collect and store blood for inflammatory biomarker analyses; they now investigate the role of gut microbiota and related metabolites in microvascular and myocardial dysfunction. Through completion of the aims, they will generate novel data on the heart-gut axis among men and women with HIV which they will then seek to investigate further in an R01 application. The ultimate goal is to improve how myocardial dysfunction and HF are understood, prevented, and treated for men and women with HIV.
Defining the Role of N-Methyladenosine during HIV Replication in Primary T Cells
N6-methyladenosine (m6A) modification of cellular RNA is critical to the regulation of its stability and translational potential and so plays an important role in the lifecycle of many viruses. This project will use a new platform for CRISPR-Cas9 gene editing in primary CD4+ T cells to knock-out and systematically evaluate the role of m6A regulatory factors in HIV replication. Changes in replication rates will be mapped to specific stages of the HIV lifecycle and select double knock-out experiments will be used to map epistatic relationships between critical factors. m6A modifications will be profiled in infected knock-out cells to determine which host factors drive specific modifications and which modifications drive phenotypic outcomes. Viral mutants and host transcriptome profiling will be used to help determine causative versus correlative effects.
These results will provide the first comprehensive analysis of the impact of m6A modifications and regulatory factors on HIV replication in primary CD4+ T cells. These experiments will not only bring clarity to an area of HIV/AIDS priority research but will also lay the groundwork for future studies examining how this network changes during and influences HIV latency and persistence.