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

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

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100934 ◽

2021 ◽

pp. 100934

Author(s):

Antonella Bugatti ◽

Francesca Caccuri ◽

Federica Filippini ◽

Cosetta Ravelli ◽

Arnaldo Caruso

Keyword(s):

B Cell ◽

Matrix Protein ◽

Hiv 1

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Expression and characterization of a B cell growth promoting polypeptide derived from the 12 kDa B cell growth factor gene (BCGF 1)

FEBS Letters ◽

10.1016/0014-5793(95)00186-d ◽

1995 ◽

Vol 361 (2-3) ◽

pp. 233-237

Author(s):

Panu E. Kovanen ◽

Kimmo Virtaneva ◽

Leena Harju ◽

Carmela Kantor ◽

Carl G. Gahmberg ◽

...

Keyword(s):

Growth Factor ◽

Cell Growth ◽

B Cell ◽

Factor Gene ◽

Growth Factor Gene ◽

B Cell Growth Factor ◽

Growth Promoting

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P-A6 Expression of HIV-1 matrix protein p17 and correlation with B cell lymphoma in HIV-1 transgenic mice

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/01.qai.0000513909.57423.ad ◽

2017 ◽

Vol 74 ◽

pp. 73

Author(s):

Virginia Carroll ◽

Mark Lafferty ◽

Luigi Marchionni ◽

Joseph Bryant ◽

Robert Gallo ◽

...

Keyword(s):

Transgenic Mice ◽

B Cell ◽

Matrix Protein ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hiv 1

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Production of a B cell growth-promoting activity, (DL)BCGF, from a cloned T cell line and its assay on the BCL1 B cell tumor.

Journal of Experimental Medicine ◽

10.1084/jem.156.6.1821 ◽

1982 ◽

Vol 156 (6) ◽

pp. 1821-1834 ◽

Cited By ~ 91

Author(s):

S L Swain ◽

R W Dutton

Keyword(s):

T Cell ◽

B Cells ◽

Cell Growth ◽

B Cell ◽

Cell Line ◽

Growth Promoting ◽

Alloreactive T Cell ◽

Culture Supernatants

Culture supernatants from a long-term alloreactive T cell line, the Dennert line C.C3.11.75 (DL) contain a B cell-growth-promoting activity. This activity can be assayed on normal B cells or on the in vivo BCL1 tumor line. We have called this activity (DL)BCGF. This activity can be distinguished from the T cell-replacing factor activity we had earlier found in DL supernates [(DL)TRF], which is required together with IL2 for the B cell plaque-forming cell response to erythrocyte antigens. The (DL)BCGF can be absorbed on untreated or glutaraldehyde-fixed BCL1. This absorption does not remove (DL)TRF activity. The production of (DL)BCGF is greatly enhanced when DL is cultured with IL2-containing supernatants. Sublines or clones of DL (DL.B10 and DL.A4) have been obtained that make large amounts of (DL)BCGF in the absence of any stimulator cells or IL2. B cells from the Xid-deficient male (DBA/2 X CBA/N)F1 mice do not respond to (DL)BCGF.

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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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