TY - JOUR
T1 - Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice
AU - Carroll, Virginia A.
AU - Lafferty, Mark K.
AU - Marchionni, Luigi
AU - Bryant, Joseph L.
AU - Gallo, Robert C.
AU - Garzino-Demo, Alfredo
N1 - Funding Information:
We also thank Dr. Albert E. Reece (University of Maryland School of Medicine) for supporting this work through the Dean's Challenge Award to Accelerate Innovation and Discovery in Medicine and the Director of the Greenebaum Cancer Center for funding support through the Cigarette Restitution Fund Pilot Grant Program. L.M. was supported by NIH Grants UL1 TR 001079 and P30CA006973. M.K.L. was supported by National Cancer Institute Institutional Training Grant 1T32 CA154274.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - 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.
AB - 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.
KW - B-cell lymphoma
KW - HIV-1
KW - Matrix protein p17
KW - RAG
KW - Transgenic mice
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U2 - 10.1073/pnas.1615258113
DO - 10.1073/pnas.1615258113
M3 - Article
C2 - 27799525
AN - SCOPUS:84995554299
SN - 0027-8424
VL - 113
SP - 13168
EP - 13173
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -