Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways.

Full Abstract

BACKGROUND: Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis in vivo unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that chronic HIV-replication in non-endothelial cells may produce novel factors that provoke angiogenic pathways. METHODS: Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth in vitro over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses. RESULTS: By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development. CONCLUSION: Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10-4 to 10-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has suppressed VEGF/VEGFR-PTK expression and promoted VEGFR-independent pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies in vivo would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel VEGF-independent angiogenic pathways.

Author information

Author/s: Rasheed, Suraiya (S); Yan, Jasper S (JS); Hussain, Adil (A); Lai, Bruce (B);

Affiliation: Laboratory of Viral Oncology and Proteomics Research Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032-3626, USA. srasheed(-atsign-)usc.edu

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of translational medicine (J Transl Med), published in England. (Language: eng)

Reference: 2009-; vol 7 (issue ) : pp 75

Dates: Created 2009/09/30; Completed 2009/10/22;

PMID: 19712456, status: MEDLINE (last retrieved date: 10/22/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Computational Biology
HIV Infections - metabolism
HIV-1 - metabolism
Humans
Lymphocyte Activation
Neovascularization, Pathologic - metabolism
Proteomics - methods

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: tat Gene Products, Human Immunodeficiency Virus (0) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.1.112)

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