AIDS-related lymphomas (ARL) account for a large proportion of malignancies in HIV-1-infected individuals and differ from other lymphomas for their high-grade and aggressive metastatic nature. Lymphangiogenesis is important in supporting proliferation and survival of lymphomas, and plays a key role in tumor dissemination. HIV-1 is not inserted within malignant cells, suggesting an indirect role for HIV in ARL incidence, which may involve HIV-1 proteins expressed in lymphatic tissue. The HIV-1 matrix protein p17 (p17) accumulates and persists in the lymph nodes of patients even under highly active antiretroviral therapy and exerts pro-angiogenic activity by binding to the chemokine receptors CXCR1 and CXCR2 expressed on endothelial cells. In light of this finding, the aim of the present study was to determine the effect of p17 on lymphangiogenesis and to elucidate the mechanism underlaying p17 effects. HIV-1 p17 promoted lymphangiogenesis of lymph node-derived lymphatic endothelial cells (LN-LECs) following nutrient starvation, after binding to CXCR1 and CXCR2 and by activating the Akt and ERK signaling pathways. Lymphangiogenesis did not occur when p17 was added to cells treated with 3-methyladenine or silenced for beclin-1, GRASP55 or Rab8a expression, thus suggesting that p17 increases autophagy-mediated unconventional proteins secretion. Indeed, we found that p17 lymphangiogenic activity was mostly mediated by autophagosome-mediated endothelin-1 secretion. Our data suggest that p17 may produce a microenvironment in the lymph node that may foster lymphoma development, progression and metastasis. Therapies targeting p17-mediated autophagy alterations may decrease lymphangiogenesis and offer new opportunities to combat ARLs.
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