Binding to PI(4,5)P2 is indispensable for secretion of B cell clonogenic HIV-1 matrix protein p17 variants

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.

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A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17

Scientific Reports ◽

10.1038/s41598-017-06848-y ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 10

Author(s):

Cinzia Giagulli ◽

Pasqualina D’Ursi ◽

Wangxiao He ◽

Simone Zorzan ◽

Francesca Caccuri ◽

...

Keyword(s):

Amino Acid ◽

B Cell ◽

Amino Acid Substitution ◽

Matrix Protein ◽

Single Amino Acid Substitution ◽

Single Amino Acid ◽

Hiv 1

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615258113 ◽

2016 ◽

Vol 113 (46) ◽

pp. 13168-13173 ◽

Cited By ~ 17

Author(s):

Virginia A. Carroll ◽

Mark K. Lafferty ◽

Luigi Marchionni ◽

Joseph L. Bryant ◽

Robert C. Gallo ◽

...

Keyword(s):

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Microarray Analysis ◽

Intracellular Signaling ◽

Matrix Protein ◽

B Cell Lymphoma ◽

Viral Proteins ◽

Increased Risk ◽

Hiv 1

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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Identification of amino acid residues critical for the B cell growth-promoting activity of HIV-1 matrix protein p17 variants

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2018.09.016 ◽

2019 ◽

Vol 1863 (1) ◽

pp. 13-24 ◽

Cited By ~ 6

Author(s):

Wangxiao He ◽

Pietro Mazzuca ◽

Weirong Yuan ◽

Kristen Varney ◽

Antonella Bugatti ◽

...

Keyword(s):

Amino Acid ◽

Cell Growth ◽

B Cell ◽

Matrix Protein ◽

Amino Acid Residues ◽

Growth Promoting ◽

Hiv 1

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F-103 A conformational switch that turns on the B cell growth- promoting activity of the HIV-1 matrix protein p17

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/01.qai.0000479626.70515.0c ◽

2016 ◽

Vol 71 ◽

pp. 61 ◽

Cited By ~ 1

Author(s):

Wangxiao He, ◽

Federica Campilongo, ◽

Francesca Caccuri, ◽

Weirong Yuan, ◽

Kristen Varney, ◽

...

Keyword(s):

Cell Growth ◽

B Cell ◽

Matrix Protein ◽

Conformational Switch ◽

Growth Promoting ◽

Hiv 1

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Association of interleukin-10 promoter genetic variants with T-cell and B-cell activation in HIV-1 infection

Retrovirology ◽

10.1186/1742-4690-9-s2-p168 ◽

2012 ◽

Vol 9 (S2) ◽

Author(s):

D Naicker ◽

B Julg ◽

C McClurg ◽

M Ghebremichael ◽

F Porichis ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Genetic Variants ◽

Cell Activation ◽

Interleukin 10 ◽

B Cell Activation ◽

Hiv 1

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IGHV1-69 B Cell Chronic Lymphocytic Leukemia Antibodies Cross-React with HIV-1 and Hepatitis C Virus Antigens as Well as Intestinal Commensal Bacteria

PLoS ONE ◽

10.1371/journal.pone.0090725 ◽

2014 ◽

Vol 9 (3) ◽

pp. e90725 ◽

Cited By ~ 23

Author(s):

Kwan-Ki Hwang ◽

Ashley M. Trama ◽

Daniel M. Kozink ◽

Xi Chen ◽

Kevin Wiehe ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

Commensal Bacteria ◽

Virus Antigens ◽

Hiv 1 ◽

Cell Chronic Lymphocytic Leukemia

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.302478 ◽

2014 ◽

Vol 34 (4) ◽

pp. 846-856 ◽

Cited By ~ 21

Author(s):

Francesca Caccuri ◽

Christine Rueckert ◽

Cinzia Giagulli ◽

Kai Schulze ◽

Daniele Basta ◽

...

Keyword(s):

Endothelial Cells ◽

Lymph Node ◽

Structure Formation ◽

Highly Active Antiretroviral Therapy ◽

Matrix Protein ◽

Lymphatic Endothelial Cells ◽

Endothelin 1 ◽

Tumor Dissemination ◽

Hiv 1

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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Functional Replacement and Positional Dependence of Homologous and Heterologous L Domains in Equine Infectious Anemia Virus Replication

Journal of Virology ◽

10.1128/jvi.76.4.1569-1577.2002 ◽

2002 ◽

Vol 76 (4) ◽

pp. 1569-1577 ◽

Cited By ~ 57

Author(s):

Feng Li ◽

Chaoping Chen ◽

Bridget A. Puffer ◽

Ronald C. Montelaro

Keyword(s):

Life Cycle ◽

Virus Particle ◽

Matrix Protein ◽

Particle Production ◽

Equine Infectious Anemia Virus ◽

Virus Infectivity ◽

Gag Protein ◽

Equine Infectious Anemia ◽

Anemia Virus ◽

Hiv 1

ABSTRACT We have previously demonstrated by Gag polyprotein budding assays that the Gag p9 protein of equine infectious anemia virus (EIAV) utilizes a unique YPDL motif as a late assembly domain (L domain) to facilitate release of the budding virus particle from the host cell plasma membrane (B. A. Puffer, L. J. Parent, J. W. Wills, and R. C. Montelaro, J. Virol. 71:6541-6546, 1997). To characterize in more detail the role of the YPDL L domain in the EIAV life cycle, we have examined the replication properties of a series of EIAV proviral mutants in which the parental YPDL L domain was replaced by a human immunodeficiency virus type 1 (HIV-1) PTAP or Rous sarcoma virus (RSV) PPPY L domain in the p9 protein or by proviruses in which the parental YPDL or HIV-1 PTAP L domain was inserted in the viral matrix protein. The replication properties of these L-domain variants were examined with respect to Gag protein expression and processing, virus particle production, and virus infectivity. The data from these experiments indicate that (i) the YPDL L domain of p9 is required for replication competence (assembly and infectivity) in equine cell cultures, including the natural target equine macrophages; (ii) all of the functions of the YPDL L domain in the EIAV life cycle can be replaced by replacement of the parental YPDL sequence in p9 with the PTAP L-domain segment of HIV-1 p6 or the PPPY L domain of RSV p2b; and (iii) the assembly, but not infectivity, functions of the EIAV proviral YPDL substitution mutants can be partially rescued by inclusions of YPDL and PTAP L-domain sequences in the C-terminal region of the EIAV MA protein. Taken together, these data demonstrate that the EIAV YPDL L domain mediates distinct functions in viral budding and infectivity and that the HIV-1 PTAP and RSV PPPY L domains can effectively facilitate these dual replication functions in the context of the p9 protein. In light of the fact that YPDL, PTAP, and PPPY domains evidently have distinct characteristic binding specificities, these observations may indicate different portals into common cellular processes that mediate EIAV budding and infectivity, respectively.

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