title: Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders.
abstract: Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L) are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB) permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat) can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1) positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Donna C
authors.initials: DC
authors.lastname: Davidson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hirschman
authors.forename: Anita
authors.initials: A
authors.lastname: Sun
authors.forename: Meera V
authors.initials: MV
authors.lastname: Singh
authors.forename: Karl
authors.initials: K
authors.lastname: Kasischke
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
mesh_terms: D015526:AIDS Dementia Complex / Q000097:blood / Q000378:metabolism* / Q000821:virology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology / Q000821:virology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000821:virology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D023201:CD40 Ligand / Q000097:blood* / Q000172:deficiency; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D015658:HIV Infections / Q000097:blood / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology; D010539:Permeability; D015539:Platelet Activation / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D054322:tat Gene Products, Human Immunodeficiency Virus; D023201:CD40 Ligand