Abstract
BackgroundHuman Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice.ResultsThe transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1β, IL-6, IL-10, IL-12p40, IL-13 and TNFα and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma.ConclusionsIncreased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1.
Highlights
Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas
HIV Tg mice developing lymphoma have abnormal lymphoid phenotypes HIV TgN (pNL43d14)26Lab (Tg26) heterozygous mice share a common phenotype characterized by cataracts, cutaneous papillomas (Figure 1A, 1B) and renal disease [20,21,22,23]
We found that Tg mice at late stages of lymphadenopathy express elevated levels of HIV proteins known to interact with B cells (p17, gp120, and nef ) [10,25,26] compared to asymptomatic Tg mice without skin lesions (Figure 2)
Summary
Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Human Immunodeficiency Virus Type I (HIV-1) infection is associated with an elevated incidence of B-cell non-Hodgkin’s lymphoma (NHL) and in recent years with Hodgkin’s lymphoma [1]. Lymphoma risk is increased approximately 150- to 250fold among HIV-infected patients compared with the general population [1,2,3]. HAL development is frequently preceded by persistent generalized lymphadenopathy, suggesting antigeninduced chronic B cell stimulation and a likely pathogenic link between B cell hyperplasia and AIDS-NHL [4,5,6]. Chronic B cell activation may drive proliferation of antigen-selected B cell clones that accumulate genetic
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