Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Apr 26:11:228.
doi: 10.3389/fnins.2017.00228. eCollection 2017.

Opinion: Inhibition of Blood-Brain Barrier Repair as a Mechanism in HIV-1 Disease

Monique E Maubert  1 , Brian Wigdahl  1   2 , Michael R Nonnemacher  1
Affiliations

Opinion: Inhibition of Blood-Brain Barrier Repair as a Mechanism in HIV-1 Disease

Monique E Maubert et al. Front Neurosci. .
No abstract available

Keywords: HIV-1; NMDAR; Tat; VEGFR; blood-brain barrier (BBB); c-Src.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Hypothetical model of the mechanisms underlying delayed blood-brain barrier repair in HIV-1 infection. Differential expression of VEGFR2 has been proposed and demonstrated on the lumen- and CNS-exposed surfaces of primary rat BMECs, in vitro (Hudson et al., 2014), lending to the possibility that this receptor may be activated by HIV-1 proteins flowing in the peripheral circulation, as well as those generated in the CNS; here, we illustrate expression of VEGFR2 on the lumen-exposed surface (orange bubble). Polarized expression of NMDAR on BMECs has not been addressed in the literature; however, in consideration that the ligands which would activate this receptor are readily found in the CNS and secreted by astrocytes (a component of the BBB in adjacent proximity with BMECs), we presume and illustrate here expression of NMDAR on the CNS-exposed surface (purple bubble). (1) HIV-1 proteins (Tat, gp120, Vpr, or Nef) bind and activate the VEGFR2 and/or NMDAR, stimulating the receptor(s) and resulting in activation of c-Src (which is associated with these receptors via adaptor proteins*), leading to a signaling cascade which is linked to downregulated expression of tight junction complex components (i.e., claudin-5, occludin, and zona occludens-1) and increased BBB permeability. (2) HIV-1 Tat protein enters BMECs and traffics to the nucleus (by its encoded nuclear localization signal) and upregulates expression of c-Src at the transcriptional level via direct modulation of Sp1 activity at the c-Src promotor. (3) HIV-1 Tat protein that enters BMECs may also be retained in the cytosol and directly bind the SH3 domain of c-Src, thus orchestrating the physical shift necessary to induce the active conformation of c-Src (i.e., phosphorylation at Y416 and de-phosphorylation at Y529) and leading to inhibition of BBB repair. (4) In addition, there may be super-activation of the NMDAR via a feedback loop between the ligand-binding face of NMDAR and cytosolic receptor-associated c-Src. Adaptor proteins: VRAP, VEGF receptor associated protein; TSAd, T-cell specific adaptor molecule; ND2, NADH dehydrogenase subunit 2.
See this image and copyright information in PMC

References

    1. Aiamkitsumrit B., Dampier W., Antell G., Rivera N., Martin-Garcia J., Pirrone V., et al. (2014). Bioinformatic analysis of HIV-1 entry and pathogenesis. Curr. HIV Res. 12, 132–161. 10.2174/1570162X12666140526121746 - DOI - PMC - PubMed
    1. Albini A., Soldi R., Giunciuglio D., Giraudo E., Benelli R., Primo L., et al. (1996). The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat. Med. 2, 1371–1375. 10.1038/nm1296-1371 - DOI - PubMed
    1. Alexandropoulos K., Baltimore D. (1996). Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130Cas-related protein, Sin. Genes Dev. 10, 1341–1355. 10.1101/gad.10.11.1341 - DOI - PubMed
    1. Andras I. E., Deli M. A., Veszelka S., Hayashi K., Hennig B., Toborek M. (2007). The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J. Cereb. Blood Flow Metab. 27, 1431–1443. 10.1038/sj.jcbfm.9600445 - DOI - PubMed
    1. Andras I. E., Pu H., Tian J., Deli M. A., Nath A., Hennig B., et al. (2005). Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J. Cereb. Blood Flow Metab. 25, 1159–1170. 10.1038/sj.jcbfm.9600115 - DOI - PubMed

LinkOut - more resources