Studies of brain tissues from people living with HIV (PLWH), as well as HIV/AIDS animal models, showed increased amyloid-? (A?) production and aggregation, amyloid plaques, increased Tau hyperphosphorylation (pTau) and formation of neurofibrillary tangles-like structures. Importantly, the presence of these Alzheimer?s Disease (AD)-like pathologies in PLWH is associated with increased neurodegeneration and HIV-associated neurocognitive impairment (HAND). The mechanisms through which HIV increase A? production, pTau pathologies, and induce AD-like central nervous system (CNS) impairment are not known. Although most PLWH who showed increased CNS amyloid plaques and pTau associated with HAND had been on long-term antiretroviral therapy (ART), the role of ART in A? and pTau production, and AD-like pathologies has not been investigated. Our in-vivo and ex-vivo studies demonstrated that HIV-1 infection significantly increased CNS levels of A?42 (the major neurotoxic component of A?) and pTau, and this was associated with neuronal damage and blood-brain barrier (BBB) injury. Significantly, we demonstrated that the CCR5 antagonist, maraviroc (MVC), abrogated HIV-induced production of A?42 and pTau, prevented HIV-induced damage to neurons and the BBB, and decreased CNS viral loads. Therefore, we hypothesize that CCR5 plays a major role in the formation of amyloid plaques and pTau pathology in PLWH and that targeting CCR5 prevents HIV-induced A? production, prevents the formation of amyloid plaques and pTau, and abrogates neuronal loss, and HAND. In these exploratory studies, we will use a validated HIV/AIDS animal model to test this hypothesis and further investigate the effects of a commonly prescribed antiretroviral (ARV) drug (azidothymidine [AZT]) on HIV- 1-induced amyloidogenesis, pTau and CNS injury (Aim-1), neuroinflammation and A? clearance (Aim-2), the metabolism of amyloid precursor proteins (APP) and Tau (Aim-3). These mechanistic studies will help determine whether HIV induce A? production by interfering with i) A? degradation and clearance, ii) APP ?-secretase or ?- secretase pathways; iii) the effectors and pathways associated with HIV-induce pTau, iv) the role of ARV (AZT), and v) whether CCR5 modulates these effects. Studies in this R21 application are very significant and address the NIH high priority research areas that focus on ?Examining the pathophysiologic mechanisms of HIV-induced CNS dysfunction in the setting of ART?. and development of novel therapeutic approaches to mitigate CNS complications of HIV infection.? The CCR5 antagonist MVC is an FDA-approved drug and our study will determine whether MVC prevents CNS A? production, formation of amyloid plaques and pTau in the setting of HIV-infection and ART, and the associated mechanisms. The results will demonstrate the role of CCR5 in HIV- induced production of A? and pTau in the CNS and provide new approaches for therapeutically targeting CCR5 to prevent HIV-1-induced amyloidogenesis, pTau pathology, neuronal injury, and neurocognitive impairments.

Public Health Relevance

People living with HIV that develop HIV-associated neurocognitive impairment (HAND) show increased brain amyloid-? (A?) production and aggregation, amyloid plaques, increased Tau hyperphosphorylation (pTau) and formation of neurofibrillary tangles-like structures; but the associated mechanisms are not known. This proposal will investigate the role of CCR5 in these pathologies and determine whether following HIV-1 infection, co-administration of antiretroviral drugs with the CCR5 antagonist maraviroc can prevent the formation of amyloid plaques and pTau, abrogate neuronal loss and HAND. These novel studies involve mechanistic in vitro and in vivo approaches and are relevant for designing therapeutic strategies to prevent or reduce Alzheimer?s Disease-like pathologies in HIV-infected individuals.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
HIV Molecular Virology, Cell Biology, and Drug Development Study Section (HVCD)
Program Officer
Rao, Vasudev
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Schools of Medicine
United States
Zip Code