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

Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13168-13173. doi: 10.1073/pnas.1615258113. Epub 2016 Oct 31.

Abstract

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.

Keywords: B-cell lymphoma; HIV-1; RAG; matrix protein p17; transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Bone Marrow / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • HIV Antigens / genetics*
  • HIV Antigens / metabolism
  • HIV-1 / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Lymph Nodes / metabolism
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Mice, Transgenic
  • gag Gene Products, Human Immunodeficiency Virus / genetics*
  • gag Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • DNA-Binding Proteins
  • HIV Antigens
  • Homeodomain Proteins
  • V(D)J recombination activating protein 2
  • gag Gene Products, Human Immunodeficiency Virus
  • p17 protein, Human Immunodeficiency Virus Type 1
  • RAG-1 protein