Abstract
HIV-1 infects T cells, but the most frequent AIDS-related lymphomas are of B-cell origin. Molecular mechanisms of HIV-1-induced oncogenic transformation of B cells remain largely unknown. HIV-1 Tat protein may participate in this process by penetrating and regulating gene expression in B cells. Both immune and cancer cells can reprogram communications between extracellular signals and intracellular signaling pathways via the Akt/mTORC1 pathway, which plays a key role in the cellular response to various stimuli including viral infection. Here, we investigated the role of HIV-1 Tat on the modulation of the Akt/mTORC1 pathway in B cells. We found that HIV-1 Tat activated the Akt/mTORC1 signaling pathway; this leads to aberrant activation of activation-induced cytidine deaminase (AICDA) due to inhibition of the AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies.
Keywords:
AICDA; Akt/mTORC1 pathway; B cells; HIV-1; Tat.
MeSH terms
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology*
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Cells, Cultured
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Cytidine Deaminase / genetics
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Cytidine Deaminase / metabolism*
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DNA Damage*
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Gene Expression Regulation*
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Humans
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-myb / genetics
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Proto-Oncogene Proteins c-myb / metabolism
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Reactive Oxygen Species / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcriptional Activation
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tat Gene Products, Human Immunodeficiency Virus / genetics
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tat Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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E2F8 protein, human
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MYB protein, human
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Proto-Oncogene Proteins c-myb
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Reactive Oxygen Species
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Repressor Proteins
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tat Gene Products, Human Immunodeficiency Virus
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase