HIV-1 matrix protein p17 promotes lymphangiogenesis and activates the endothelin-1/endothelin B receptor axis.
OBJECTIVE
AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein.


RESULTS
Human primary lymph node-derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node-derived lymphatic endothelial cells and activating the Akt/extracellular signal-regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node-derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation.


CONCLUSIONS
Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.
From the Microbiology Section, Department of Molecular and Translational Medicine (F.C., C.G., D.B., S.Z., S.F., A.C.) and Section of Vascular Surgery, Department of Medical and Surgical Sciences (E.C.), University of Brescia, Brescia, Italy; Animal Models and Retroviral Vaccine Section, National Cancer Institute, National Institutes of Health, Bethesda, MD (F.C.); Department of Vaccinology and Applied Microbiology, Helmholtz Centre of Infection Research, Braunschweig, Germany (C.R., K.S., C.A.G.); Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende (Cosenza), Italy (S.M.); and School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom (M.S.).
Francesca
F
Caccuri
Christine
C
Rueckert
Cinzia
C
Giagulli
Kai
K
Schulze
Daniele
D
Basta
Sonia
S
Zicari
Stefania
S
Marsico
Edoardo
E
Cervi
Simona
S
Fiorentini
Mark
M
Slevin
Carlos A
CA
Guzman
Arnaldo
A
Caruso
D000818:Animals; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology; D019332:Endothelin-1 / Q000378:metabolism*; D004729:Endothelium, Lymphatic / Q000378:metabolism* / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015488:HIV Antigens / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D016483:Lymphoma, AIDS-Related / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013997:Time Factors; D014945:Wound Healing; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D019332:Endothelin-1; D015488:HIV Antigens; D044023:Receptor, Endothelin B; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
HIV-1; MAP kinase signaling pathways; angiogenesis factor; endothelin-1; lymphatic endothelial cells; p17 matrix protein