HIV-1 infected individuals on combination antiretroviral therapy (cART) are living longer than the pre-cART era, however these individuals are at an increased risk of developing neurocognitive disorders referred to as HIV-1-associated neurocognitive disorders (HAND). HIV-1 infects a great number of cells, yielding proviral DNA. And while cART reduces viral replication, it has no effect on these early viral gene products such as transactivator of transcription (Tat). Tat upregulates inflammatory mediators, stimulating peripheral monocytes to permeate into the central nervous system (CNS). The underlying mechanisms as to how monocytes are able to cross the blood brain barrier (BBB) remain elusive. Previously, our lab has shown that in HAND patients, their cerebrospinal fluid (CSF) and plasma contained abnormally high levels of soluble CD40L (sCD40L) and we have shown that mice injected with physiologically relevant concentrations of Tat had significantly greater levels of sCD40L in their plasma than non-treated mice. In addition, our lab has reported that CD40L receptor, CD40, were present on brain microvascular endothelial cells (BMVEC) and thus this interaction promoted the infiltration of monocytes across the BBB, in vitro. Further, our in vivo studies revealed that Tat induces BBB permeability in mice in a CD40L dependent manner as a result of atypical activation of platelets, a major source of sCD40L, because BBB permeability is reversed after platelet depletion. Overall, these data provide me with a rational framework to test my hypothesis that the virally encoded proteins induce CD40-CD40L signaling to disrupt neurovascular homeostasis and thereby compromising BBB integrity, yielding subsequent neurologic damages that are consistent with the CNS manifestations associated with HAND. The development of new therapeutic approaches can be expected at the completion of this study to address HAND and possibly other neurocognitive disorders not HAND related.

Public Health Relevance

Study results obtained are expected to exert a high impact on the neuroAIDS field by elevating scientific knowledge and revealing how HIV-1 induces CNS inflammation in infected patients and by validating novel therapeutic targets for HAND, which are also viable in other neurodegenerative disorders that are secondary to BBB disruption.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS086256-01
Application #
8648207
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Wong, May
Project Start
2013-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$35,832
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627