R01DA055488

Persistent HIV-1 Expression and Microglia Dysfunction - Abstract/Project Summary

Microglia are long-lived central nervous system (CNS)-resident innate immune cells that have critical immune surveillance functions and homeostatic functions in the brain, including clearance of pathogens and maintaining integrity of neuronal synapses.

Microglia are targeted by HIV, have been proposed to be a reservoir for HIV persistent infection, and are mediators of HIV-associated inflammation and neuropathogenesis. Importantly, microglia dysfunction is proposed to contribute to HIV-associated neurodegeneration and inflammation even when HIV replication is suppressed during antiretroviral treatments.

The mechanisms, direct or indirect, that drive microglia to promote inflammation during HIV infection have not been elucidated. In this study, we will utilize a primary microglia-neuron co-culture model derived from pluripotent stem cells to test the hypothesis that HIV in microglia establishes persistently infected microglia that express aberrant viral RNAs, including those that retain intronic sequences, which mediate inflammasome activation to drive microglia dysfunction, CNS inflammation, and neuronal injury.

Our preliminary data supporting our hypothesis includes results demonstrating that primary macrophages harbor defective HIV proviruses and, despite harboring deletions and mutations that attenuate virus production, generate HIV RNAs. Furthermore, our previous work established the potential role of HIV intron-containing RNA in activating inflammatory activities in macrophages and microglia.

Specific questions addressed in this proposal include:
1) What is the status of proviruses in HIV-infected microglia?
2) What mechanisms drive persistent expression of HIV RNA in microglia?
3) What are the mechanisms that trigger inflammasome activation in HIV-activated macrophages?

Completion of this project will provide general insights into the impact of HIV-1 persistence and expression in the context of microglia. Importantly, these studies will provide insights into mechanisms that contribute to HIV-1 CNS comorbidities, which persist even with ART, and could lead to new targets and strategies for treatments that will improve the lives of people living with HIV.

Boston Medical Center Corporation

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Boston, Massachusetts 021182908 United States

Single Zip Code

Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain (R01 Clinical Trial Not Allowed) (RFA-MH-20-701)

Amendment Since initial award the total obligations have increased 388% from $759,381 to $3,708,561.