As the leading cause of age-related disabilities, neurocognitive diseases such as Alzheimer?s disease (AD) and other dementias are poised to significantly impact global health care as the population of people aged 60 and older nearly doubles in the next three decades. One group at a significantly greater risk of age-related neurodegenerative diseases are HIV-infected (HIV+) patients. An estimated 50% of HIV+ patients on antiretroviral therapy (ART) develop mild to severe impairments in brain function with age. Designated as HIV- associated neurocognitive disorders (HAND), this syndrome is expected to increase dramatically in the next decade as more than 70% of Americans with HIV turn 50 and older, and ART becomes more widely available in the developing world. The imminent global impact of HAND underscores the urgent need to understand the mechanistic basis of neurodegeneration in HIV+ patients on ART and devise effective interventions. This proposal is focused on understanding the immune mechanisms underlying age-related neurodegeneration following HIV infection using a robust rhesus model which recapitulates salient aspects of HIV pathophysiology in humans.
In Aim 1 of this research project, we will establish the role of monocytes in neurodegeneration; specifically, pro-inflammatory monocytes.
In Aim 2, we will determine the role of Th1, and Th17 CD4 T cell subsets in neurodegeneration. Considering that HIV and HIV-associated neuroinflammation interfere with amyloid and tau metabolism, in Aim 3 we will investigate whether pathological AD markers are induced during HIV-associated neuroinflammation. The collective complementary expertise of the investigators and collaborators in tackling the scientific questions posed in the application will facilitate an in-depth understanding of the immune and synaptic mechanisms underlying neurodegeneration. These preclinical studies will establish the mechanistic and experimental foundations to identify predictive biomarkers of HAND and subsequently enable opportunities in a relevant and tractable model for testing novel, targeted interventions as adjunctive therapy to ART. Only by quantifying measures of SIV-induced HAND sequelae in macaques can parameters of intervention be evaluated for efficacy prior to human studies.

Public Health Relevance

An estimated 50% of HIV-infected patients on antiretroviral therapy develop neurocognitive disorders. This proposal uses robust powerful and complementary approaches to understand the mechanisms underlying age- related neurodegeneration during HIV infection. The findings will enable rational design of interventions to ameliorate or prevent neurocognitive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
3RF1AG061001-01S1
Application #
10094931
Study Section
Program Officer
Mackiewicz, Miroslaw
Project Start
2018-09-30
Project End
2023-03-31
Budget Start
2020-06-01
Budget End
2023-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618