title: Smoothened Agonist Reduces Human Immunodeficiency Virus Type-1-Induced Blood-Brain Barrier Breakdown in Humanized Mice.
abstract: Human Immunodeficiency Virus type-1 (HIV)-associated neurocognitive disorder is characterized by recruitment of activated/infected leukocytes into the CNS via disrupted Blood Brain Barrier (BBB) that contributes to persistent neuro-inflammation. In this report, humanized NOD/scid-IL2Rγc(null) mice were used to establish that impaired Sonic hedgehog (Shh) signaling is associated with loss of BBB function and neurological damage, and that modulating Shh signaling can rescue these detrimental effects. Plasma viral load, p24 levels and CD4(+) T cells were measured as markers of productive HIV infection. These mice also showed impaired exclusion of Evans blue dye from the brain, increased plasma levels of S100B, an astrocytic protein, and down-regulation of tight junction proteins Occludin and Claudin5, collectively indicating BBB dysfunction. Further, brain tissue from HIV(+) mice indicated reduced synaptic density, neuronal atrophy, microglial activation, and astrocytosis. Importantly, reduced expression of Shh and Gli1 was also observed in these mice, demonstrating diminished Shh signaling. Administration of Shh mimetic, smoothened agonist (SAG) restored BBB integrity and also abated the neuropathology in infected mice. Together, our results suggest a neuroprotective role for Shh signaling in the context of HIV infection, underscoring the therapeutic potential of SAG in controlling HAND pathogenesis.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.
authors.forename: Vir B
authors.initials: VB
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.
authors.forename: Meera V
authors.initials: MV
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA.
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002452:Cell Count; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D003514:Cyclohexylamines / Q000494:pharmacology*; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D003514:Cyclohexylamines; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D018696:Neuroprotective Agents; D062793:Occludin; C568986:Ocln protein, mouse; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; C468918:SAG compound; C465570:Shh protein, mouse; D013876:Thiophenes; D000071676:Zinc Finger Protein GLI1