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 epidermal growth factor receptor-1 (EGFR1) 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 down-stream 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.

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Affiliations

  1. School of Healthcare Science, John Dalton Building, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK

    • Donghui Liu
    • , Yasmin Zeinolabediny
    • , Glenn Ferris
    • , Wen-Hui Fang
    • , Ria Weston
    • , Jerzy Krupinski
    • , Baoqiang Guo
    •  & Mark Slevin
  2. University of Medicine and Pharmacy, Targu Mures, Romania

    • Donghui Liu
    • , Yasmin Zeinolabediny
    •  & Mark Slevin
  3. Department of Molecular and Translational Medicine, Section of Microbiology, University of Brescia Medical School, Brescia, Italy

    • Francesca Caccuri
    •  & Arnaldo Caruso
  4. Hospital Universitari Mútua de Terrassa, Department of Neurology, Terrassa, Barcelona, Spain

    • Jerzy Krupinski
  5. Department of Molecular Biochemistry and Pharmacology, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy

    • Laura Colombo
    •  & Mario Salmona
  6. Instituto De Investigaciones Biomedicas De Barcelona, CSIC, Barcelona, Spain

    • Ruben Corpas
    • , Sara Sarroca
    •  & Coral Sanfeliu
  7. Weifang Medical University, Weifang, China

    • Xianwei Zeng
    •  & Mark Slevin

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https://doi.org/10.1038/s41374-018-0147-z