p17 from HIV induces brain endothelial cell angiogenesis through EGFR-1-mediated cell signalling activation

Abstract

HIV-associated neurocognitive disorder in HIV patients substantially reduces their quality of life. We previously showed that the HIV matrix protein, p17 could stimulate lymph-angiogenesis in vitro potentially contributing to lymphoma tumour growth and in addition is associated with vascular activation in neuro-degenerating brain tissue; here, therefore, we have investigated the detailed molecular mechanisms of this action. We performed in vitro cell culture, angiogenesis experiments, phospho-protein microarrays and Western blotting to identify cellular signalling induced by p17 within human brain endothelial cells (HbMEC), and inhibitor studies to block p17-induced vascular growth. We also characterised the effects of hippocampal CA1 injection of p17 on EGFR-1 expression linked to our murine model of dementia. p17 strongly induced angiogenesis of HbMEC (migration, tube formation and spheroid growth). p17 concomitantly increased phosphorylation of EGFR1 as well as downstream intermediates ERK1/2, FAK, PLC-γ and PKC-β whilst an inhibitor peptide of EGFR, blocked cell signalling and angiogenesis. Finally, Mice that showed reduced cognitive function and behavioural deficiencies after p17 injection, demonstrated that p17 localised in cortical microvessels and also neurones many of which stained positive for p-EGFR1 by histology/IHC. This work provides strong support that p17 may be involved in initiating and/or perpetuating vascular tissue pathophysiology associated with comorbidity in HIV patients.

Hedgehog Signaling: Implications in Cancers and Viral Infections

“…We discuss the possible role of HH signaling in viral latency, virus reservoir maintenance, entry, replication, pathogenesis, infected cell proliferation, infection progression, pathogen recognition in the host, and the immune response of the host, exit of the pathogen and memory of the host immune mediators (Figure 4). HIV [159,160], HCV [161,162], HBV [163], EBV, and KSHV [164][165][166] utilize VEGF to maintain the vascularity of the tumors and infected cell proliferation. HH signaling plays an indispensable role in vascular development in mouse embryos via VEGF and NOTCH signaling [167].…”

“…Maturation of VEGF-induced new vessels in the cornea involves a platelet derived growth factor (PDGF)-SHH axis that mediates PDGF-BB-mediated smooth muscle cell (SMC) migration by inducing ERK1/2 and PI3Kγ activation [177]. Elegant studies described that KSHV utilizes host PDGF receptor- HIV [159,160], HCV [161,162], HBV [163], EBV, and KSHV [164][165][166] utilize VEGF to maintain the vascularity of the tumors and infected cell proliferation. HH signaling plays an indispensable role in vascular development in mouse embryos via VEGF and NOTCH signaling [167].…”

Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin

“…Whether this functional epitope actually marks the pathogenic difference between HIV-1 and HIV-2 needs further investigation. to the chemokine receptors CXCR1 and CXCR2, the physiological receptors for interleukin (IL)-8 (15,16), to thrombin receptor (17) and possibly to other, still unknown, receptors (18,19). Interaction of p17 with its receptors is followed by specific intracellular signaling pathways which are responsible for different biological activities (11,(15)(16)(17)(18)(19).…”

“…to the chemokine receptors CXCR1 and CXCR2, the physiological receptors for interleukin (IL)-8 (15,16), to thrombin receptor (17) and possibly to other, still unknown, receptors (18,19). Interaction of p17 with its receptors is followed by specific intracellular signaling pathways which are responsible for different biological activities (11,(15)(16)(17)(18)(19). It is therefore likely that certain sites on p17 are constrained to allow functional epitopes to perform unavoidable interactions aimed to favor a better HIV-1 replication and spreading.…”

Receptor for Activated C Kinase 1 promotes cervical cancer lymph node metastasis via glycolysis-dependent AKT/mTOR signaling pathway

“…Growing evidence suggests that LNM is a complex process involving mechanical forces within the tumor and host tissues as well as molecular factors initiated by tumor cell proliferation, cytokine production, and lymphangiogenesis [5] . Lymphangiogenesis involves the migration of endothelial cells into tumors and formation of new lymph vessels [6,7] . However, lymphangiogenesis and its regulatory mechanisms in CC remain unclear.…”