This proposal seeks to define early changes to monocyte/macrophages (MO) phenotype and function induced during acute HIV infection (AHI) and to determine the role of timing of early initiation of combination antiretroviral therapy (cART in preventing long term HIV-induced alterations on MO profile and HIV infection of MO. In the context of initial exposure to HIV which establishes the central nervous system (CNS) reservoir of infection, the proposed aims will characterize persistent HIV reservoirs which could contribute to our understanding to develop innovative strategies to cure the body of HIV-1 infection. Changes to MO profile and the degree of MO HIV burden are closely linked to development of neurocognitive impairment (NCI). Because brain injury involving perturbed MO populations may occur very early upon exposure to HIV, understanding the natural history of MO perturbations in the earliest stages of HIV infection is critical to eradicating HIV and strategizing concepts of intervention. Alterations in monocyte homeostasis have profound clinical implications in chronic HIV and our lab has recently identified a perturbed phenotypic and functional MO profiles in chronic HIV that contributes to NCI as well as demonstrated that MO harbor high HIV burden that is associated with NCI. In collaboration with investigators of the NIH-funded RV254/SEARCH 010 cohort with over 100 AHI cases in Bangkok, Thailand, the proposed study presents a unique opportunity to define the earliest changes to monocytes during AHI by leveraging specimens and biological measurements including cerebrospinal fluid (CSF) inflammatory assessments and magnetic resonance spectroscopy (MRS) of the brain. We have established the timing of infection on average 2 weeks from onset of HIV exposure and defined the pattern of systemic and CSF cellular responses and HIV viral burden. We propose to define the earliest timepoint in AHI where MO features and viral burden rise to high levels resembling chronic infection and relate this to (1) early neuroinvasion that will be characterized by measurable circulating markers of CNS inflammation and by brain parenchymal inflammation as detected by MRS, (2) baseline viral penetration assessed by CSF/Plasma HIV viral load ratio and (3) assess the effects of early suppressive cART and telmisartan + cART intensification on MO inflammation.

Public Health Relevance

This study will investigate the early changes to monocyte/macrophage phenotype and function during acute HIV infection that could be important in the development of cognitive impairment. We hypothesize that understanding these key mechanisms will be important for developing new paradigms for eradicating HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH104141-01
Application #
8737160
Study Section
Special Emphasis Panel (ZRG1-AARR-D (50))
Program Officer
Joseph, Jeymohan
Project Start
2014-06-01
Project End
2019-03-31
Budget Start
2014-06-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$626,402
Indirect Cost
$186,336
Name
University of Hawaii
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822