Chronic immune activation persists in a subset of HIV-infected individuals who are virally suppressed. The consequences of this activation include cognitive impairment, cardiovascular disease and metabolic abnormalities. While a functioning immune response is important to maintain good health, continued activation can be detrimental. Our work has concentrated on monocyte activation in HIV infection and the initiation as well as consequences of chronic immune activation, including cognitive impairment and downstream cellular effects. Interferon alpha (IFN?) and lipopolysaccharide (LPS) from HIV infection activate monocytes that release exosomes, which are membrane bound nanoparticles that contain functional proteins, mRNA and abundant small noncoding microRNAs (miR). These exosomes alone can enter and influence recipient cells. We have characterized the exosomes from activated monocytes and identified miRs that influence immune activation associated with HIV infection. Our overall hypothesis is that targeted exosomes carrying specific antagomiRs will decrease peripheral activation and may decrease HIV infection by silencing activated monocytes. This proposal will engineer exosomes targeted to CD16+ monocytes and containing antagomiRs to silence the activation associated with several miRs that cause downstream brain and cardiovascular inflammation. We will utilize a functional in vitro assay to confirm silencing. Once we identify antagomiRs that can effectively silence the inflammatory response we will use these targeted exosomes in a humanized HIV mouse model and evaluate the in vivo response.

Public Health Relevance

In spite of effective therapy for HIV infection, some individuals experience cognitive impairment and other HIV-associated co-morbidities. This is thought to be from chronic inflammation initiated by HIV infection. This proposal looks at a new mechanism to target inflammation by inhibiting factors at the cellular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI138923-01A1
Application #
9617614
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Lawrence, Diane M
Project Start
2018-05-15
Project End
2020-04-30
Budget Start
2018-05-15
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121