HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Caccuri, Francesca; Rueckert, Christine; Giagulli, Cinzia; Schulze, Kai; Basta, Daniele; Zicari, Sonia; Marsico, Stefania; Cervi, Edoardo; Fiorentini, Simona; Slevin, Mark; Guzmán, Carlos A.; Caruso, Arnaldo

doi:10.1161/atvbaha.113.302478

Cited by 36 publications

(47 citation statements)

References 47 publications

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“…Recent data have highlighted the capability of p17 to also promote both angiogenesis (25,26) and lymphangiogenesis (26,27), which are essential in supporting proliferation and survival of lymphoma, as well as tumor cell dissemination (28). Altogether, these evidences corroborate the hypothesis that p17 may play a key role in producing a microenvironment that fosters lymphoma development, progression, and metastasis.…”

Section: Discussionmentioning

confidence: 54%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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102

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Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.non-Hodgkin lymphoma | HIV-1 matrix protein p17 | AIDS | p17 variants | B-cell clonogenicity

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Section: Discussionmentioning

confidence: 54%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…Matrix p17 may influence tumor development at one or more stages, including early B-cell development in BM, B-cell growth in the periphery, and/or support angiogenesis/lymphangiogenesis (18)(19)(20)(21)(22). Although we cannot completely exclude the role of other viral proteins, we did not detect gp120 or Nef in lymph nodes in early disease stages.…”

Section: Discussionmentioning

confidence: 56%

“…Human IL-8 receptors, CXCR1/2, are putative receptors for HIV matrix protein p17 and are thought to be important for the proangiogenic activity observed in vitro with endothelial cells, as well as the chemotactic activity observed with human primary monocytes and B cells (19,21). Although the expression of CXCR1/2 on human B cells is limited, up-regulation of the receptors on peripheral blood B cells from HIV-infected patients or by cytokines in vitro has been reported (34) (35).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, proviral sequences for variant p17s that display B-cell growth-promoting activity can be found in HIV-NHL tissues, suggesting a role for variant p17s in lymphoma pathogenesis (12). In addition to its effects on B cells, p17 can induce angiogenesis/lymphangiogenesis in vitro and in vivo (20)(21)(22). In addition, cumulative viremia during cART is known to be a strong predictor of HIV-NHL, especially for BL (23).…”

Section: Significancementioning

confidence: 99%

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Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

Carroll

Lafferty

Marchionni

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 infection is associated with increased risk for B-cell lymphomas. How HIV infection promotes the development of lymphoma is unclear, but it may involve chronic B-cell activation, inflammation, and/or impaired immunity, possibly leading to a loss of control of oncogenic viruses and reduced tumor immunosurveillance. We hypothesized that HIV structural proteins may contribute to lymphomagenesis directly, because they can persist long term in lymph nodes in the absence of viral replication. The HIV-1 transgenic mouse Tg26 carries a noninfectious HIV-1 provirus lacking part of the gag-pol region, thus constituting a model for studying the effects of viral products in pathogenesis. Approximately 15% of Tg26 mice spontaneously develop leukemia/lymphoma. We investigated which viral proteins are associated with the development of leukemia/lymphoma in the Tg26 mouse model, and performed microarray analysis on RNA from spleen and lymph nodes to identify potential mechanisms of lymphomagenesis. Of the viral proteins examined, only expression of HIV-1 matrix protein p17 was associated with leukemia/lymphoma development and was highly expressed in bone marrow before disease. The tumor cells resembled pro-B cells, and were CD19(+)IgM(-)IgD(-)CD93(+)CD43(+)CD21(-)CD23(-)VpreB(+)CXCR4(+) Consistent with the pro-B-cell stage of B-cell development, microarray analysis revealed enrichment of transcripts, including Rag1, Rag2, CD93, Vpreb1, Vpreb3, and Igll1 We confirmed RAG1 expression in Tg26 tumors, and hypothesized that HIV-1 matrix protein p17 may directly induce RAG1 in B cells. Stimulation of human activated B cells with p17 enhanced RAG1 expression in three of seven donors, suggesting that intracellular signaling by p17 may lead to genomic instability and transformation

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“…Extracellularly, the viral protein displays potent angiogenic and lymphangiogenic activity, and its ability to promote the formation of mature neovessels (vasculogenesis) was found as potent as that exerted by vascular endothelial growth factor A (VEGF-A) (16,17). The activity of p17 occurs after binding to the chemokine (C-X-C motif) receptor 1 (CXCR1) and CXCR2 expressed on endothelial cells (ECs), thus mimicking the prolymphangiogenic activity of the CXCR1/2 natural ligand interleukin-8 (18).…”

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confidence: 99%

Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis

Mazzuca

Marsico

Schulze

et al. 2017

J Virol

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AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1-infected (HIV ϩ ) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV ϩ patients under successful cART. The viral protein displays potent lymphangiogenic activity in vitro and in vivo. This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node-derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy-incompetent mice. Our findings reveal a previously unrecognized role of autophagy in lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumordriven lymphangiogenesis in HIV ϩ patients.IMPORTANCE AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV ϩ ) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced lymphangiogenesis occurs in the lymph nodes of HIV ϩ patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting lymphangiogenesis. Here, we show that p17 promotes lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs.KEYWORDS HIV-1 matrix protein p17, autophagy, lymphatic endothelial cells, lymphangiogenesis, AIDS-related lymphoma

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HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

Cited by 36 publications

References 47 publications

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis

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