Dysregulation of sonic hedgehog pathway and pericytes in the brain after lentiviral infection

Abstract

Background Impairment of the blood–brain barrier (BBB) has been associated with cognitive decline in many CNS diseases, including HIV-associated neurocognitive disorders (HAND). Recent research suggests an important role for the Sonic hedgehog (Shh) signaling pathway in the maintenance of BBB integrity under both physiological and pathological conditions. Methods In the present study, we sought to examine the expression of Shh and its downstream effectors in relation to brain pericytes and BBB integrity in HIV-infected humans and rhesus macaques infected with simian immunodeficiency virus (SIV), an animal model of HIV infection and CNS disease. Cortical brain tissues from uninfected ( n = 4) and SIV-infected macaques with (SIVE, n = 6) or without encephalitis (SIVnoE, n = 4) were examined using multi-label, semi-quantitative immunofluorescence microscopy of Shh, netrin-1, tight junction protein zona occludens 1 (ZO1), glial fibrillary acidic protein, CD163, platelet-derived growth factor receptor b (PDGFRB), glucose transporter 1, fibrinogen, and SIV Gag p28. Results While Shh presence in the brain persisted during HIV/SIV infection, both netrin-1 immunoreactivity and the size of PDGFRB+ pericytes, a cellular source of netrin-1, were increased around non-lesion-associated vessels in encephalitis compared to uninfected brain or brain without encephalitis, but were completely absent in encephalitic lesions. Hypertrophied pericytes were strongly localized in areas of fibrinogen extravasation and showed the presence of intracellular SIVp28 and HIVp24 by immunofluorescence in all SIV and HIV encephalitis cases examined, respectively. Conclusions The lack of pericytes and netrin-1 in encephalitic lesions, in line with downregulation of ZO1 on the fenestrated endothelium, suggests that pericyte loss, despite the strong presence of Shh, contributes to HIV/SIV-induced BBB disruption and neuropathogenesis in HAND. Electronic supplementary material The online version of this article (10.1186/s12974-019-1463-y) contains supplementary material, which is available to authorized users.

Occludin, caveolin‐1, and Alix form a multi‐protein complex and regulate HIV‐1 infection of brain pericytes

“…19 Several studies confirmed these results, identifying brain pericytes as an important player in HIV-1 infection. 11,20,22,23,44 We recently proposed that pericytes might be HIV-1 reservoir cells in the CNS, as they can alternate from productive HIV-1 infection to latent steps of the viral cycle. 22 The importance of these findings stems from the fact that infection of pericytes may provide a gateway for HIV-1 to enter brain parenchyma.…”

“…17,18 While it is believed that HIV-1 disrupts the BBB permeability by functional and structural hindrance of TJs, recent evidence indicates that HIV-1 can also infect brain pericytes. [19][20][21][22][23] Infected pericytes can release the virus into the microenvironment, potentially providing a previously unrecognized mechanism of HIV-1 entry into the CNS directly related to pathobiology of the BBB. [20][21][22] Occludin (ocln) is a transmembrane TJ protein 24 ; however, recent evidence has shown an important role of this protein in regulating cellular metabolism through influencing AMPK protein kinase activity, ATP production, and glucose uptake.…”

Astrocytic Sonic Hedgehog Alleviates Intracerebral Hemorrhagic Brain Injury via Modulation of Blood-Brain Barrier Integrity

“…After ICH, activated astrocytes are involved in the development of cytotoxic edema via expressing aquaporin-4, a water channel protein released from the end-feet of astrocytes (Laird et al, 2010). The role of astrocytes is known to be crucial to the SHH signaling pathway as astrocytes are considered a primary cellular source of SHH production in CNS injury (Amankulor et al, 2009;Alvarez et al, 2011;He et al, 2013;Bohannon et al, 2019). The upregulation of SHH in astrocytes was reported in TBI, EAE, and LPS injury models (Wang et al, 2008;Amankulor et al, 2009).…”

The Paradox of HIV Blood–Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies

“…Part of this permeability change may be due to a reduction in pericyte coverage of the brain endothelium that may lead to monocyte neuro-infiltration, including trafficking of HIV-infected cells, and to elevated levels of proinflammatory cytokines [ 19 ]. Additionally, dysfunction of the BBB has been confirmed in the form of pericyte loss, contributing to the HIV-induced BBB dysregulation and associated comorbidities [ 20 ]. The importance of these events stems from the fact that endothelial cells are sensitive to inflammatory insult [ 21 ].…”

“…Latently infected pericytes were exposed to histone deacetylase inhibitors and tumor necrosis factor that resulted in increased p24 and HIV RNA levels, confirming a viral reactivation [ 34 ]. Pericytes express both CD4 and chemokine coreceptors, allowing them to be directly infected by HIV [ 20 , 35 ].…”