Synthetic HIV-1 matrix protein p17-based AT20-KLH therapeutic immunization in HIV-1-infected patients receiving antiretroviral treatment: A phase I safety and immunogenicity study

Iaria, Maria Luisa; Fiorentini, Simona; Focà, Emanuele; Zicari, Sonia; Giagulli, Cinzia; Caccuri, Francesca; Francisci, Daniela; Perri, Giovanni Di; Castelli, Francesco; Baldelli, Franco; Caruso, Arnaldo

doi:10.1016/j.vaccine.2013.12.051

Cited by 24 publications

(16 citation statements)

References 27 publications

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“…Moreover, it is now becoming evident that p17 and its variants, may play a role in B-cell lymphoma growth and dissemination195758. At present, the p17 protein is the target of a therapeutic vaccine aimed at boosting and better directing the immune response against the functional epitope involved in the p17/p17 receptors interactions59. At the same time, inhibitors of the p17/PI(4,5)P 2 interaction60 as well as inhibitors of γ-secretase61 are major targets for drug development.…”

Section: Discussionmentioning

confidence: 99%

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

Caccuri

Iaria

Campilongo

et al. 2016

Sci Rep

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The human immune deficiency virus type 1 (HIV-1) matrix protein p17 (p17), although devoid of a signal sequence, is released by infected cells and detected in blood and in different organs and tissues even in HIV-1-infected patients undergoing successful combined antiretroviral therapy (cART). Extracellularly, p17 deregulates the function of different cells involved in AIDS pathogenesis. The mechanism of p17 secretion, particularly during HIV-1 latency, still remains to be elucidated. A recent study showed that HIV-1-infected cells can produce Gag without spreading infection in a model of viral latency. Here we show that in Gag-expressing cells, secretion of biologically active p17 takes place at the plasma membrane and occurs following its interaction with phosphatidylinositol-(4,5)-bisphosphate and its subsequent cleavage from the precursor Gag (Pr55Gag) operated by cellular aspartyl proteases. These enzymes operate a more complex Gag polypeptide proteolysis than the HIV-1 protease, thus hypothetically generating slightly truncated or elongated p17s in their C-terminus. A 17 C-terminal residues excised p17 was found to be structurally and functionally identical to the full-length p17 demonstrating that the final C-terminal region of p17 is irrelevant for the protein’s biological activity. These findings offer new opportunities to identify treatment strategies for inhibiting p17 release in the extracellular microenvironment.

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Section: Discussionmentioning

confidence: 99%

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

Caccuri

Iaria

Campilongo

et al. 2016

Sci Rep

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“…An important finding of the present study is the demonstration that the serum of an HIV positive patient who underwent a vaccination program [25] with a p17 protein contains anti-p17 antibodies which effectively neutralize the biological effects of the viral protein. The fact that a serum taken from the same HIV infected person before vaccination, but not a serum from an HIV negative healthy subject, was partially effective in reversing some effects of p17, is consistent with the presence of low title p17 neutralizing antibodies [18].…”

Section: Discussionmentioning

confidence: 73%

“…Having shown that the HIV matrix protein p17 regulates the expression of proteins involved in HSC functions, such as collagen deposition and contraction, we have next investigated whether these effects could be reversed using the serum of an HIV positive patient who underwent a vaccination with a p17 peptide [18], [25]. As illustrated in Figure 3A–C, exposure of LX2 cells to p17 neutralizing antibodies retained in the sera of a vaccinated patient completely abrogates the effects of p17 in terms of induction of collagen-I, α-SMA and endothelin-1.…”

Section: Resultsmentioning

confidence: 99%

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The HIV Matrix Protein p17 Promotes the Activation of Human Hepatic Stellate Cells through Interactions with CXCR2 and Syndecan-2

et al. 2014

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BackgroundThe human immunodeficiency virus type 1 (HIV-1) p17 is a matrix protein involved in virus life's cycle. CXCR2 and Syndecan-2, the two major coreceptors for the p17 protein, are expressed in hepatic stellate cells (HSCs), a key cell type involved in matrix deposition in liver fibrotic disorders.AimIn this report we have investigated the in vitro impact of p17 on HSCs transdifferentiation and function and underlying signaling pathways involved in these processes.MethodsLX-2 cells, a human HSC line, and primary HSC were challenged with p17 and expressions of fibrogenic markers and of p17 receptors were assessed by qRT-PCR and Western blot. Downstream intracellular signaling pathways were evaluated with qRT-PCR and Western blot as well as after pre-treatment with specific pathway inhibitors.ResultsExposure of LX2 cells to p17 increases their contractile force, reshapes the cytoskeleton fibers and upregulates the expression of transdifferentiation markers including αSMA, COL1α1 and endothelin-1 through the activation of Jak/STAT and Rho signaling pathways. These effects are lost in HSCs pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide. Confocal laser microscopy studies demonstrates that CXCR2 and syndecan-2 co-associate at the plasma membrane after exposure to p17. Immunostaining of HIV/HCV liver biopsies from co-infected patients reveals that the progression of liver fibrosis correlates with a reduced expression of CXCR2.ConclusionsThe HIV matrix protein p17 is pro-fibrogenic through its interactions both with CXCR2 and syndecan-2 on activated HSCs.

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“…Our data suggest a novel strategy to inhibit ARL development and metastasis by directly targeting p17 and its B-cell growth-promoting variants. This may be achieved by using a specific therapeutic vaccine aimed to generate a neutralizing p17 response (45) or by using p17-specific drugs (46). There is increasing interest in the role that autophagic dysregulation may play in different vascular pathologies (21).…”

Section: Discussionmentioning

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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Synthetic HIV-1 matrix protein p17-based AT20-KLH therapeutic immunization in HIV-1-infected patients receiving antiretroviral treatment: A phase I safety and immunogenicity study

Cited by 24 publications

References 27 publications

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

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

The HIV Matrix Protein p17 Promotes the Activation of Human Hepatic Stellate Cells through Interactions with CXCR2 and Syndecan-2

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

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