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.
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.