Abstract
BackgroundA close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents.MethodsHIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas.In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects.ResultsOur results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down-regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells.ConclusionsOur findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs.These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression.
Highlights
A close association between Human Immunodeficiency Virus (HIV) infection and the development of cancer exists
AIDS-associated lymphomas are of B-lymphoid origin in at least 95% of all cases described despite the fact that HIV infects T-lymphocytes [1], raising the question whether HIV may have a direct role in B-cell lymphomagenesis
Our results show that DNA Methyltransferase 1 (DNMT1), DNMT3a/b are up-regulated in B-cell lymphomas, and that this relies on down-regulation of specific miRNAs
Summary
A close association between HIV infection and the development of cancer exists. the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents. A close association between Human Immunodeficiency Virus (HIV) infection and the development of a number of cancers, NHL being the second most common, has been described. The frequencies of different subpopulations of B-cells have been reported altered in the presence of HIV Reviewed in [2]. These changes include increased frequency of activated and terminally differentiated B-cells expressing low levels of CD21 that have been associated with ongoing viral replication [3,4], a decreased frequency of memory B-cells that is not reversed by antiretroviral therapy [5], and an increased frequency of immature/transitional B-cells that has been associated with CD4+ T-cell lymphopenia [6,7,8]. Changes in the microenvironment of the host cells have been recorded following HIV infection [11], as well as chronic immune activation and dysfunctional cytokine production that have been described throughout all stages of HIV-1 infection [12]
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