The progressive loss of cognitive abilities in HIV-1-infected individuals, which is currently referred to as HIV-1-associated neurocognitive disorders (HAND;also popularly known as neuroAIDS), remains a substantial clinical concern. Recent studies have shown that the disruption of the blood-brain barrier (BBB) plays a major role in the progression of HAND. However, the underlying mechanisms that regulate the BBB during HIV-1 infection remain poorly defined. In this competitive renewal, we propose to test the hypothesis that BBB permeability is the result of deregulated trans-cellular communication between brain endothelial cells and astrocytes, following enduring effects of HIV-1 proteins on CD40/CD40L signaling. Our project seeks to shift current research and clinical paradigms by defining novel intracellular signaling targets, such as the CD40/CD40L axis and the Sonic hedgehog (Shh) pathway, that play potentially crucial roles in regulating BBB permeability in response to HIV-1 infection, and through functional validation of these targets by using novel anti-Shh drugs as novel therapeutics for HAND. Here we intend to integrate a comprehensive analysis of cellular responses due to HIV-1 with novel methodologies such as intravital multiphoton microscopy in a humanized mouse model.
In Aim 1, we will test the hypothesis that CD40/CD40L signaling plays an important role in HIV-1-induced BBB permeability in vivo.
Aim 2 will examine whether CD40/CD40L signaling disrupts trans-cellular communication between astrocytes and brain endothelial cells. Finally, in Aim 3 we will investigate whether targeting the Shh pathway renders mice resistant to BBB permeability induced by HIV-1 Tat in a CD40L-dependent manner. The results obtained in these studies are expected to exert a high impact on the neuroAIDS field on three counts: (1) by advancing scientific knowledge and revealing how HIV-1 induces CNS inflammation in infected patients, (2) by promoting novel methodologies and animal models, and (3) by validating novel therapeutic targets for HAND, which are also viable in other neurodegenerative disorders that are secondary to BBB disruption.
This proposal focuses on learning how early proteins produced by HIV-1 alters cellular signaling mechanisms in a manner that causes inflammation in the brain and contributes to nerodegeneration ultimately leading to the loss of cognitive functions in infected patients. Such understanding is expected to advance the development of novel therapeutic approaches for this disorder.
|Singh, Meera V; Davidson, Donna C; Jackson, Joseph W et al. (2014) Characterization of platelet-monocyte complexes in HIV-1-infected individuals: possible role in HIV-associated neuroinflammation. J Immunol 192:4674-84|
|Davidson, Donna C; Schifitto, Giovanni; Maggirwar, Sanjay B (2013) Valproic acid inhibits the release of soluble CD40L induced by non-nucleoside reverse transcriptase inhibitors in human immunodeficiency virus infected individuals. PLoS One 8:e59950|
|Davidson, Donna C; Jackson, Joseph W; Maggirwar, Sanjay B (2013) Targeting platelet-derived soluble CD40 ligand: a new treatment strategy for HIV-associated neuroinflammation? J Neuroinflammation 10:144|
|Singh, Meera V; Davidson, Donna C; Kiebala, Michelle et al. (2012) Detection of circulating platelet-monocyte complexes in persons infected with human immunodeficiency virus type-1. J Virol Methods 181:170-6|
|Morrell, Craig N; Maggirwar, Sanjay B (2011) Recently recognized platelet agonists. Curr Opin Hematol 18:309-14|
|Kiebala, Michelle; Maggirwar, Sanjay B (2011) Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells. PLoS One 6:e18633|
|Xu, Xiangbin; Steere, Rachel R; Fedorchuk, Christine A et al. (2011) Activation of epidermal growth factor receptor is required for NTHi-induced NF-?B-dependent inflammation. PLoS One 6:e28216|
|Cao, Shengbo; Wu, Chengxiang; Yang, Yongbo et al. (2011) Lentiviral vector-mediated stable expression of sTNFR-Fc in human macrophage and neuronal cells as a potential therapy for neuroAIDS. J Neuroinflammation 8:48|
|Davidson, Donna C; Hirschman, Michael P; Spinelli, Sherry L et al. (2011) Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals. J Immunol 186:584-91|
|Spinelli, Sherry L; Casey, Ann E; Pollock, Stephen J et al. (2010) Platelets and megakaryocytes contain functional nuclear factor-kappaB. Arterioscler Thromb Vasc Biol 30:591-8|
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