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

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 of c-MYC and AICDA were significantly enhanced in lymphoma cells, up to 2-fold for c-MYC and up to 4-fold for AICDA, 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 of c-MYC was enhanced in the presence of Nef in a dose-dependent manner, the same was not observed for AICDA. 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.

HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells

“…HIV proteins could also contribute to the development of lymphomas in HIV-infected patients. Indeed, HIV-Nef significantly promotes AICDA expression along with MYC expression in Burkitt lymphoma [ 54 ].…”

Long noncoding RNAs (lncRNAs) in HIV-mediated carcinogenesis: Role in cell homeostasis, cell survival processes and drug resistance

“…To potentiate tumorigenesis, Tat protein transactivates the Human papillomavirus (HPV) long control region and enhances the expression of HPV-18 oncoprotein, E7, in cervical cancer cells [ 7 ]. Additionally, HIV oncoprotein, Negative factor (Nef), also promote cancer by increasing the expression of cellular myelocytomatosis (c-MYC) expression, which led to genomic instability in Burkitt lymphoma [ 100 ].…”

HIV-1 Transactivator of Transcription (Tat) Co-operates With AP-1 Factors to Enhance c-MYC Transcription

“…Factors attributable to this include chronic inflammation, and B-cell hyperactivation as a result of viral persistence, as well as co-infection with other oncogenic viruses ( Robbins et al, 2015 ; Abudulai et al, 2016 ; Hart et al, 2018 ). In recent years, HIV and its viral components have been directly implicated in driving oncogenesis, and this is strongly evidenced in the development of KS, and more recently in B-cell derived malignancies ( Xue et al, 2014 ; Cesarman et al, 2019 ; Santerre et al, 2019 ; Mdletshe et al, 2020 ). Although HIV-1 is known to only infect a subset of human cells, namely CD4 + cells, soluble HIV-1 proteins are detectable in the serum of HIV-infected individuals, and shown to invade and/or bind to the receptors of uninfected cells including B lymphocytes and endothelial cells ( Lazzi et al, 2002 ; Eugenin et al, 2007 ; Xu et al, 2009 ; Lamers et al, 2010 ; Musinova et al, 2016 ; Anand et al, 2018 ).…”

“…Although HIV-1 is known to only infect a subset of human cells, namely CD4 + cells, soluble HIV-1 proteins are detectable in the serum of HIV-infected individuals, and shown to invade and/or bind to the receptors of uninfected cells including B lymphocytes and endothelial cells ( Lazzi et al, 2002 ; Eugenin et al, 2007 ; Xu et al, 2009 ; Lamers et al, 2010 ; Musinova et al, 2016 ; Anand et al, 2018 ). Upon entering bystander cells they interfere with host gene expression and other cellular processes, which are contributing factors to cellular transformation, and ultimately the development of HIV-associated cancers ( Martorelli et al, 2015 ; Carroll et al, 2016 ; Santerre et al, 2019 ; Mdletshe et al, 2020 ).…”