After almost three decades of AIDS epidemic, we are still challenged with the fact that more than one out of three people with productive infection of HIV-1 develops some form of HIV-1 associated neurocognitive disorder (HAND), which remains refractory to the conventional antiviral therapeutics. In addition, the clinical symptoms of HAND are found to coexist with those of other systemic inflammatory diseases in a significant proportion of patients, some of which are associated with a higher number of activated platelets in the circulation. This may suggest that a common underlying mechanism is at work in these infected individuals. In this respect, HIV-infected patients exhibit increased numbers of activated platelets in the plasma in a manner that relates to the severity of the immunologic deficit, however, it is unknown whether platelets play a pivotal role in the pathogenesis of HAND. Here we demonstrate that the systemic administration of physiologically relevant levels of Tat produces evidence of platelet activation in the plasma, followed by enhanced permeability of the BBB and inflammation in the CNS. These effects were abolished when Tat was administered to animals that had first been depleted of platelets, supporting the notion that platelets might play a crucial role in HAND. Based on these findings, we hypothesize that the activation of peripheral platelets by effector molecules released by HIV-1-infected cells elicits abnormal effects on brain microvascular endothelial cells (BMVEC), thereby altering blood-brain barrier (BBB) integrity and exacerbating inflammation in the CNS. Three fundamentally critical questions are addressed in this proposal. The first is whether inflammatory mediators released by HIV-infected cells also target other immune effector cells, such as platelets (Aim 1). Second, if activated platelets in turn activate BMVEC to stimulate inflammatory vascular changes that are connected with BBB permeability (Aim 2);and last whether the effects caused by platelets facilitate frequent passage of peripheral blood monocytes through an otherwise normal BBB (Aim 3). The obvious corollary to this is whether therapeutic manipulation of platelet activity provides protection from neurologic damages induced by HIV. Thus, the experiments proposed herein have great translational potential for the development of new therapeutic strategies for neuroAIDS.

Public Health Relevance

It is speculated that a common mechanism is engaged by HIV-1 to stimulate inflammatory disorders in various body compartments. This notion will be tested by investigating whether the abnormal activation of blood platelets accounts for the observed neurologic deficits in HIV-infected individuals. The outcome of these studies is expected to further our understanding of disease, which ultimately will lead to new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066801-05
Application #
8608607
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2010-02-15
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
Singh, Meera V; Weber, Emily A; Singh, Vir B et al. (2017) Preventive and therapeutic challenges in combating Zika virus infection: are we getting any closer? J Neurovirol 23:347-357
Singh, Vir B; Singh, Meera V; Piekna-Przybylska, Dorota et al. (2017) Sonic Hedgehog mimetic prevents leukocyte infiltration into the CNS during acute HIV infection. Sci Rep 7:9578
Piekna-Przybylska, Dorota; Sharma, Gaurav; Maggirwar, Sanjay B et al. (2017) Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1. Cell Cycle 16:968-978
Connor, Ryan; Jones, Letitia D; Qiu, Xing et al. (2017) Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection. J Leukoc Biol 102:953-964
Piepenbrink, Michael S; Samuel, Memorie; Zheng, Bo et al. (2016) Humoral Dysregulation Associated with Increased Systemic Inflammation among Injection Heroin Users. PLoS One 11:e0158641
Singh, Vir B; Singh, Meera V; Gorantla, Santhi et al. (2016) Smoothened Agonist Reduces Human Immunodeficiency Virus Type-1-Induced Blood-Brain Barrier Breakdown in Humanized Mice. Sci Rep 6:26876
Jackson, Joseph W; Singh, Meera V; Singh, Vir B et al. (2016) Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis. PLoS One 11:e0157115
Jones, Letitia D; Jackson, Joseph W; Maggirwar, Sanjay B (2016) Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction. PLoS One 11:e0151702
De Jesús Andino, Francisco; Jones, Letitia; Maggirwar, Sanjay B et al. (2016) Frog Virus 3 dissemination in the brain of tadpoles, but not in adult Xenopus, involves blood brain barrier dysfunction. Sci Rep 6:22508
Singh, Vir B; Wooten, Alicia K; Jackson, Joseph W et al. (2015) Investigating the role of ankyrin-rich membrane spanning protein in human immunodeficiency virus type-1 Tat-induced microglia activation. J Neurovirol 21:186-98

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