title: Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction.
abstract: The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND) is increasing. In these individuals, the integrity of the blood-brain barrier (BBB) is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L) is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT) mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1). As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Letitia D
authors.initials: LD
authors.lastname: Jones
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Jackson
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
mesh_terms: D015526:AIDS Dementia Complex / Q000503:physiopathology; D000818:Animals; D001792:Blood Platelets / Q000502:physiology* / Q000821:virology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D023201:CD40 Ligand / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000503:physiopathology*; D015497:HIV-1 / Q000235:genetics; D009052:Leukemia Virus, Murine / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019562:Viral Load
chemical_list: D015699:HIV Envelope Protein gp120; D023201:CD40 Ligand