Progression of HIV-associated neurocognitive disorders (HAND) is associated with trafficking of human immunodeficiency virus type-1 (HIV) infected leukocytes into the central nervous system (CNS), which appears to begin as early as 8 days post-infection. However, at this time the cerebrospinal fluid (CSF) levels of MCP- 1/CCL2 were found to be unchanged, thus making it challenging to explain how HIV-infected leukocytes are mobilized during this early stage of infection, which leads to the establishment of CNS reservoirs. Interestingly, our supporting data reveal that these early events noted in acutely infected individuals can be closely mimicked in HIV-infected humanized mice. Importantly, we observed marked platelet activation in these mice within 1 to 4 weeks of infection -as reported in persons with acute HIV infection-which was tightly correlated with the rate of human peripheral leukocytes migration into the CNS. Based on these findings, we posit that HIV triggers a push and pull mechanism throughout the course of infection that enables trafficking of infected leukocytes into the CNS. In this model, we propose that the activated platelets initially provide a push by directly interacting with infected leukocytes to facilitate migrationof leukocytes across the blood-brain barrier (BBB). This follows with a rapid increase in the production of chemokines within the CNS thus establishing a complementing pull that recruits additional infected/activated leukocytes into the CNS. This model then, in full accordance with the available literature, accounts for how neuroinflammation is initiated, and maintained, in HIV-infected individuals. These studies will bring together five established investigators and one emerging investigator with proven expertise in virology, platelet/monocyte biology, animal models of HIV-infection, therapeutics, and HIV clinical research. Importantly, proposed studies will leverage research infrastructure offered by the University of Rochester Center for AIDS Research (UR-CFAR). Our studies contain great potential for clinical translation, in which, our investigations will reveal how early intervention may impact viral reservoirs in the CNS, and how a two-prong approach in which targeting viral entry into the CNS while dampening secondary inflammation would yield long-term neuroprotection and tissue homeostasis.

Public Health Relevance

This proposal focuses on learning how small blood cells known as platelets promote migration of HIV- infected white cells into the brain during acute and chronic stages of HIV infection ultimately leading to the establishment of viral reservoirs in the brain and development of neurologic disorders in HIV-infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066801-08
Application #
9433694
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2010-02-15
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
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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