Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Caccuri, Francesca; Iaria, Maria Luisa; Campilongo, Federica; Varney, Kristen M.; Rossi, Alessandro; Mitola, Stefania; Schiarea, Silvia; Bugatti, Antonella; Mazzuca, Pietro; Giagulli, Cinzia; Fiorentini, Simona; Lu, Wuyuan; Salmona, Mario; Caruso, Arnaldo

doi:10.1038/srep38027

Cited by 16 publications

(28 citation statements)

References 71 publications

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“…This is not surprising since latently HIV-1-infected resting T cells are capable of producing gag proteins in a model of HIV-1 latency [27]. Moreover, recent data show that p17 is continuously released into the extracellular space from HIV-1-infected cells even in the absence of viral protease, following its cellular aspartyl protease-dependent cleavage from the gag precursor protein [28].…”

Section: Introductionmentioning

confidence: 96%

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Bugatti

Marsico

Mazzuca

et al. 2020

IJMS

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Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.

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Section: Introductionmentioning

confidence: 96%

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Bugatti

Marsico

Mazzuca

et al. 2020

IJMS

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“…Interestingly, p17 is continuously released in the extracellular space even in the absence of viral replication and viral protease activity [45] and is detected at nanomolar concentrations in the blood of HIV + patients even in the presence of anti-p17 antibodies [46].…”

Section: Hiv-1 Structural Proteinsmentioning

confidence: 99%

Endothelial Cell Dysfunction in HIV-1 Infection

Mazzuca¹,

Caruso²,

Caccuri³

2018

Endothelial Dysfunction - Old Concepts and New Challenges

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Human immunodeficiency virus type 1 (HIV-1) promotes a generalized immune activation that alters the physiology of cells that are not sensitive to viral infection. Endothelial cells (ECs) display heavy dysfunctions in HIV-1-seropositive (HIV +) patients that persist even in patients under successful combined antiretroviral therapy (cART). In vivo studies failed to demonstrate the presence of replicating virus in ECs suggesting that a direct role of the virus in vascular dysfunction is unlikely. This finding paves the way to the hypothesis of a key role of molecules released in the microenvironment by HIV-1-infected cells in sustaining aberrant EC function. Here we review the current understanding regarding the contribution of HIV-1 infection to vascular dysfunction. In particular, we argue that different HIV-1 proteins may play a key role in driving and sustaining inflammation and EC dysregulation, thus underlining the need to target them for therapeutic benefit.

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“…Purified endotoxin (lipopolysaccharide)-free recombinant p17 (from clone BH10 of clade B isolate), NHL-a105 (a B-cell clonogenic p17 variant derived from an HIV ϩ patient with NHL) (35), glutathione S-transferase (GST), and the HIV-1 capsid protein p24 (p24) were produced as previously described (14,35,48). The absence of endotoxin contamination (Ͻ0.25 endotoxin units/ml) in protein preparations was assessed by the Limulus amebocyte assay (Associates of Cape Cod, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…This is not surprising since latently HIV-1-infected resting T cells are capable of producing HIV-1 proteins without supporting spreading infection (13). Moreover, recent data show the capability of gag-expressing cells to release p17 in the absence of viral protease, following its cellular aspartyl proteasedependent cleavage from the gag precursor protein (14). Overall, these findings indicate that p17, as well as other viral structural proteins, could be produced by cells potentially residing in the germinal centers, even in the absence of viral replication.…”

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confidence: 97%

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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Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Cited by 16 publications

References 71 publications

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17

Endothelial Cell Dysfunction in HIV-1 Infection

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

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