Sonic Hedgehog mimetic prevents leukocyte infiltration into the CNS during acute HIV infection

Vir B. Singh, Meera V. Singh, Dorota Piekna-Przybylska, Santhi Gorantla, Larisa Y. Poluektova, Sanjay B. Maggirwar

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Infiltration of infected leukocytes culminates in establishment of a brain niche for Human Immunodeficiency Virus (HIV) during acute phase of infection, initiating an ongoing cascade of persistent viral replication and inflammation, that causes irreversible neuronal injury and HIV associated neurocognitive disease (HAND). In this study, humanized mice were treated with Smoothened Agonist (SAG), a Sonic Hedgehog (Shh) mimetic in order to fortify blood brain barrier (BBB) and dampen leukocyte extravasation into CNS during AHI. Results indicate that SAG treatment reduced viral burden in the CNS immediately after HIV transmission, but also conferred extended neuroprotection via increased BBB integrity (elevated levels of tight-junction protein, Claudin 5, and reduced S100B levels in periphery). These mice also showed healthier neurons with thick, uniform dendrites and reduced numbers of activated astrocytes. Additional in vitro experiments suggested SAG treatment was not associated with the establishment or reversal of latency in the target cells. Altogether, these findings validate neuroprotective role of Shh signaling and highlight the therapeutic potential of Shh mimetics against CNS complications associated with HIV infection. Further our results strongly demonstrate that pharmacological interventions to reduce leukocyte mobilization during early HIV infection, can provide prolonged neuroprotection, which might significantly delay the onset of HAND.

Original languageEnglish (US)
Article number9578
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Hedgehogs
Virus Diseases
Leukocytes
HIV
Blood-Brain Barrier
Claudin-5
Tight Junction Proteins
Early Ambulation
Dendrites
Viral Load
Astrocytes
Therapeutics
Pharmacology
Inflammation
Neurons
Wounds and Injuries
Brain
Infection
SAG compound

ASJC Scopus subject areas

  • General

Cite this

Sonic Hedgehog mimetic prevents leukocyte infiltration into the CNS during acute HIV infection. / Singh, Vir B.; Singh, Meera V.; Piekna-Przybylska, Dorota; Gorantla, Santhi; Poluektova, Larisa Y.; Maggirwar, Sanjay B.

In: Scientific reports, Vol. 7, No. 1, 9578, 01.12.2017.

Research output: Contribution to journalArticle

Singh, Vir B. ; Singh, Meera V. ; Piekna-Przybylska, Dorota ; Gorantla, Santhi ; Poluektova, Larisa Y. ; Maggirwar, Sanjay B. / Sonic Hedgehog mimetic prevents leukocyte infiltration into the CNS during acute HIV infection. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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