期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13168-13173
DOI：10.1073/pnas.1615258113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNon-Hodgkin lymphomas are associated with HIV infection. Current hypotheses on lymphomagenesis, based on immunosuppression and/or activation and/or inflammation, are generic and do not provide mechanistic, testable models. Here we show that several HIV proteins are expressed in a HIV transgenic mouse model of lymphoma, but only Matrix/p17 is consistently expressed at high levels even in early disease stages. Microarray analyses of gene expression showed an enrichment of recombination-activating genes (Rag1/2) in mouse lymphoma tissue. When activated human B cells were treated with p17, induction of RAG1 expression was observed in three of seven donors. Taken together, and in the context of the literature, our results point to the involvement of p17 in supporting B-cell growth and genetic instability. 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.
