Abstract
HIV-1 infection often leads to the development of co-morbidities including cancer. Burkitt lymphoma (BL) is one of the most over-represented non-Hodgkin lymphoma among HIV-infected individuals, and displays a highly aggressive phenotype in this population group, with comparatively poorer outcomes, despite these patients being on anti-retroviral therapy. Accumulating evidence indicates that the molecular pathogenesis of HIV-associated malignancies is unique, with components of the virus playing an active role in driving oncogenesis, and in order to improve patient prognosis and treatment, a better understanding of disease pathobiology and progression is needed. In this study, we found HIV-1 Tat to be localized within the tumor cells of BL patients, and enhanced expression of oncogenic c-MYC in these cells. Using luciferase reporter assays we show that HIV-1 Tat enhances the c-MYC gene promoter activity and that this is partially mediated via two AP-1 binding elements located at positions -1128 and -1375 bp, as revealed by mutagenesis experiments. We further demonstrate, using pull-down assays, that Tat can exist within a protein complex with the AP-1 factor JunB, and that this complex can bind these AP-1 sites within the c-MYC promoter, as shown by in vivo chromatin immunoprecipitation assays. Therefore, these findings show that in HIV-infected individuals, Tat infiltrates B-cells, where it can enhance the expression of oncogenic factors, which contributes toward the more aggressive disease phenotype observed in these patients.
Highlights
People infected with HIV are at significantly higher risk of developing cancer
This risk has diminished since the introduction of Highly Active Antiretroviral Therapy (HAART), HIV-infected individuals remain over-represented within specific cancer groups, such as Kaposi’s sarcoma (KS), subtypes of non-Hodgkin lymphomas (NHL) and cervical cancer (Guiguet et al, 2009), when compared to the general population
HIV-1 Tat Is Detectable in the Tumors of HIV Positive Burkitt lymphoma (BL) Patients, and Tat-Expression in BL Cells Leads to Enhanced c-MYC Expression
Summary
People infected with HIV are at significantly higher risk of developing cancer This risk has diminished since the introduction of Highly Active Antiretroviral Therapy (HAART), HIV-infected individuals remain over-represented within specific cancer groups, such as Kaposi’s sarcoma (KS), subtypes of non-Hodgkin lymphomas (NHL) and cervical cancer (Guiguet et al, 2009), when compared to the general population. These individuals display more severe disease and have lower survival rates, often despite maintaining CD4+ T cell count at nearnormal levels (Powles et al, 2009; Coghill et al, 2015). Upon entering bystander cells they interfere with host gene expression and other cellular processes, which are contributing factors to cellular transformation, and the development of HIVassociated cancers (Martorelli et al, 2015; Carroll et al, 2016; Santerre et al, 2019; Mdletshe et al, 2020)
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