HIV-1 matrix protein p17 binds to monocytes and selectively stimulates MCP-1 secretion: role of transcriptional factor AP-1

Marini, Elena; Tiberio, Laura; Caracciolo, Sonia; Tosti, Giorgio; Guzmán, Carlos A.; Schiaffonati, Luisa; Fiorentini, Simona; Caruso, Arnaldo

doi:10.1111/j.1462-5822.2007.01073.x

Cited by 43 publications

(43 citation statements)

References 49 publications

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“…Blood was collected from healthy donors, who gave informed consent for this research according to the Declaration of Helsinki. Human monocytes were isolated from whole blood as previously described (7). Primary B lymphocytes were isolated by negative selection from peripheral blood mononuclear cells obtained from healthy donors using the B cell isolation kit II from Miltenyi Biotec according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…It is released in the extracellular space from HIV-1-infected cells and is easily detected in the plasma and tissue specimens of patients (2,3), including those successfully treated with highly active antiretroviral therapy) (4). Extracellularly, p17 has been found to deregulate the biological activities of many different cells that are directly or indirectly involved in AIDS pathogenesis (3,(5)(6)(7)(8)(9)(10). All p17 activities occur after interaction between the functional epitope (AT20) located at the N-terminal region (amino acids 11 to 30) of the viral protein with receptors expressed on different target cells (5).…”

mentioning

confidence: 99%

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Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Matrix Proteins Specify Different Capabilities To Modulate B Cell Growth

Caccuri

Giagulli

Reichelt

et al. 2014

J Virol

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Exogenous HIV-1 matrix protein p17 (p17) deregulates the function of different cells after its N-terminal loop (AT20) binding to the chemokine receptors CXCR1 and CXCR2. One site within AT20 has been recently found to be the major determinant of viral fitness following transmission of simian immunodeficiency virus (SIV) to the human host. Therefore, we sought to determine whether SIV matrix protein (MA) was already capable of interacting with CXCR1 and CXCR2 and mimic p17 biological activities rather than this being a newly acquired function during host adaptation. We show here that SIV MA binds with the same affinity of p17 to CXCR1 and CXCR2 and displays both p17 proangiogenic on human primary endothelial cells and chemotactic activity on human primary monocytes and B cells. However, SIV MA exhibited a higher degree of plasticity than p17 in the C terminus, a region known to play a role in modulating B cell growth. Indeed, in contrast to p17, SIV MA was found to activate the phosphatidylinositol 3-kinase/Akt signaling pathway and strongly promote B cell proliferation and clonogenic activity. Interestingly, we have recently highlighted the existence of a Ugandan HIV-1 strain-derived p17 variant (S75X) with the same B cell growth-promoting activity of SIV MA. Computational modeling allowed us to hypothesize an altered C terminus/core region interaction behind SIV MA and S75X activity. Our findings suggest the appearance of a structural constraint in the p17 C terminus that controls B cell growth, which may help to elucidate the evolutionary trajectory of HIV-1. IMPORTANCEThe HIV-1 matrix protein p17 (p17) deregulates the biological activities of different cells after binding to the chemokine receptors CXCR1 and CXCR2. The p17 functional domain responsible for receptors interaction includes an amino acid which is considered the major determinant of SIV replication in humans. Therefore, we sought to determine whether SIV matrix protein (SIV MA) already had the ability to bind to both chemokine receptors rather than being a function newly acquired during host adaptation. We show here that SIV MA binds to CXCR1 and CXCR2 and fully mimics the p17 proangiogenic and chemokine activity. However, it differs from p17 in its ability to signal into B cells and promote B cell growth and clonogenicity. Computational analysis suggests that the accumulation of mutations in the C-terminal region may have led to a further SIV MA adaptation to the human host. This finding in turn sheds light on the evolutionary trajectory of HIV-1.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Matrix Proteins Specify Different Capabilities To Modulate B Cell Growth

Caccuri

Giagulli

Reichelt

et al. 2014

J Virol

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“…[15][16][17][18] Experiments performed on human primary monocytes have shown that p17 exerts a chemokine-like activity. This activity was mediated by p17 binding to chemokine (C-X-C motif) receptor-1 (CXCR1), and the viral protein was found to mimic some of the interleukin-8 (IL-8) biological activities.…”

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confidence: 99%

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

Caccuri

Rueckert

Giagulli

et al. 2014

ATVB

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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. Approach and 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.

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“…Several studies reported JNK activation by a number of viruses, including human immunodeficiency virus type 1 (HIV-1) (31), herpes simplex virus (30), influenza virus (26), adenovirus (27), varicella-zoster virus (48), and Kaposi's sarcoma-associated herpesvirus (35). The activity of JNK has been linked to virus replication mainly through the effect of AP-1 on transcriptional regulation of viral genes (26)(27)(28)42). Other observations linked JNK inactivation with a reduction in the number of herpesvirus genome copies, suggesting that JNK may play a role at a step before the start of viral replication (9,35).…”

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JNK1 Is Required for Lentivirus Entry and Gene Transfer

Lee

Padmashali

Andreadis

2011

J Virol

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Although a lot of progress has been made in development of lentiviral vectors for gene therapy, the interactions of these vectors with cellular factors have not been explored adequately. Here we show that lentivirus infection phosphorylates JNK and that blocking the kinase activity of JNK decreases gene transfer in a dose-dependent manner, regardless of the viral envelope glycoprotein. Knockdown by small interfering RNA (siRNA) revealed that JNK1 but not JNK2 was required for productive gene transfer. The effect of JNK on gene transfer was not due to changes in the cell cycle, as JNK knockdown did not affect the cell cycle profile of target cells and even increased cell proliferation. In addition, confluent cell monolayers also exhibited JNK phosphorylation upon lentivirus infection and a dose-dependent decrease in gene transfer efficiency upon JNK inhibition. On the other hand, JNK activation was necessary for lentivirus internalization into the cell cytoplasm, while inhibition of JNK activity decreased virus entry without affecting binding to the cell surface. These experiments suggest that JNK is required for lentivirus entry into target cells and may have implications for gene transfer or for development of antiviral agents.

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HIV-1 matrix protein p17 binds to monocytes and selectively stimulates MCP-1 secretion: role of transcriptional factor AP-1

Cited by 43 publications

References 49 publications

Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Matrix Proteins Specify Different Capabilities To Modulate B Cell Growth

Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 1 Matrix Proteins Specify Different Capabilities To Modulate B Cell Growth

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

JNK1 Is Required for Lentivirus Entry and Gene Transfer

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