Sunday, May 18, 2025
5/18/2025
PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5 - PROJECT ABSTRACT Brain tissues from people living with HIV (PLWH) showed evidence of Alzheimer’s Disease (AD)-like pathologies, including increased neurotoxic amyloid-b (Ab40/42), amyloid plaques and Tau hyperphosphorylation (pTau) associated with neurodegeneration and HIV-associated neurocognitive disorders (HAND). The mechanisms through which HIV increase Ab, pTau, and induce AD-like central nervous system (CNS) impairment are not known. Although most PLWH with CNS Ab plaques and pTau had been on long-term antiretroviral therapy (ART), the role of ART in pTau and Ab production, and AD-like pathologies has not been investigated. Findings from our R21 studies, using in vitro, in vivo and ex vivo approaches, demonstrated that HIV-1 significantly increased CNS Ab42 and pTau in humanized mice, and this was associated with significantly 1) increased expression and activation/activity of b-secretase-1 (BACE1), soluble (s)APPb (amyloidogenic pathway effectors), and GSK3b (kinase that phosphorylates Tau); 2) reduced expression/activity of neprilysin (NEP, Ab-degrading enzyme); 3) increased blood-brain barrier (BBB) expression of the receptor for advanced glycation end products (RAGE, mediates Ab CNS influx), and reduced BBB expression of low-density lipoprotein receptor–related protein-1 (LRP1, mediates CNS Ab efflux); and 4) increased neuroinflammation, neuronal damage and BBB injury. We demonstrated that LRP1 and CCR5 mediated Ab transport through the BBB, that AZT potentiated HIV-induced upregulation/activation of BACE1, sAPPb and GSK3b, and that AZT blocked NEP expression/activity. Significantly, the CCR5 antagonist maraviroc (MVC) abrogated these HIV- and AZT- induced effects. Thus, we hypothesize that CCR5, via LRP1, plays a major role in Ab formation, transport, and catabolism, amyloidogenesis and pTau in PLWH, and that targeting CCR5 prevents HIV-induced Ab and pTau, increases Ab CNS efflux, and abrogates CNS injury and HAND. Using a validated HIV/AIDS animal model, primary human cells and human brain tissues, we will test this hypothesis and further investigate the effects of commonly prescribed antiretroviral (ARV) drugs (AZT, TDF) on HIV-induced activation of BACE1 and APP amyloidogenic pathway, Tau metabolism, and CNS injury (Aim-1); Ab transport, degradation, clearance, and neuroinflammation (Aim-2); and associated BBB transcriptomic and epigenomic signatures (Aim-3). These mechanistic studies will help determine whether HIV induces amyloidogenesis by i) activating BACE1 pathways to increase Ab production or ii) by interfering with LRP1-mediated Ab transport, degradation, clearance; iii) the role of ARVs; iv) whether CCR5 modulates these effects; and v) characterize the brain vascular transcriptome and epigenome associated with HIV/ARVs-induced dysregulation and MVC protective effects. Our proposed studies are of high-impact, translational significance, 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.”
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