HIV Nef enhances the expression of oncogenic c-MYC and activation-induced cytidine deaminase in Burkitt lymphoma cells, promoting genomic instability

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Abstract Background Non-Hodgkin lymphoma is of high prevalence among HIV-infected people. In particular, the incidence of HIV-associated Burkitt lymphoma (BL) remains high despite the advent of Highly Active Anti-Retroviral Therapy. Recent evidence shows that serum-soluble HIV proteins can enhance oncogenesis, particularly in lymphoid tissues. This study sought to define the role of HIV protein Negative regulatory factor (Nef) in BL development by assessing its effect on key lymphoma driver genes. Methods A recombinant Nef protein was used to assess changes in expressions of activation-induced cytidine deaminase (AICDA/AID) and c-MYC in B lymphocytes exposed extracellularly to the protein. Additionally, changes in the promoter activities of these genes were measured using a Nef-expressing cellular model and reporter assays. Confocal microscopy was used to observe c-MYC and AID expression and localization, and genomic integrity via the recruitment of phosphorylated γ-H2AX, in Nef-exposed cells. Results mRNA transcription ofc-MYCandAICDAwere significantly enhanced in lymphoma cells, up to 2-fold forc-MYCand up to 4-fold forAICDA, when exposed to varying concentrations of Nef (0–1000 ng/ml) and for different periods of time (3, 6 and 12 h). The protein expressions of AID and c-MYC followed a similar pattern and these effects were specific to BL but not lymphoblastoid cells. While the promoter activity ofc-MYCwas enhanced in the presence of Nef in a dose-dependent manner, the same was not observed forAICDA. Both AID and c-MYC accumulated within the cytoplasmic and nuclear spaces of Nef-exposed lymphoma cells, with a concomitant increase in DNA double strand breaks within the genome. Conclusions Exposure to HIV Nef leads to significant increases in AID and c-MYC, leading to genomic instability, potentially enhancing the oncogenic potential of Burkitt lymphoma. Our findings align with that of others to show that HIV proteins can directly contribute to the development and pathogenesis of HIV-associated lymphoma and accounts for the elevated incidence of BL observed in the HIV-infected population.

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