Human Immunodeficiency Virus Tat Protein Aids V Region Somatic Hypermutation in Human B Cells

mBio

Zhi Duan¹  Matthew D. Scharff¹  Guojun Yu¹  Manxia Fan¹  Xiaohua Wang¹ 

[1] Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA;

关键词: AID;    AIDS;    B cell;    HIV;    Tat;    somatic hypermutation;   

DOI  :  10.1128/mBio.02315-17

来源: DOAJ

【 摘 要 】

ABSTRACT Long-term survivors of human immunodeficiency virus (HIV) infection have been shown to have a greatly increased incidence of B cell lymphomas. This increased lymphomagenesis suggests some link between HIV infection and the destabilization of the host B cell genome, a phenomenon also suggested by the extraordinary high frequency of mutation, insertion, and deletion in the broadly neutralizing HIV antibodies. Since HIV does not infect B cells, the molecular mechanisms of this genomic instability remain to be fully defined. Here, we demonstrate that the cell membrane-permeable HIV Tat proteins enhance activation-induced deaminase (AID)-mediated somatic hypermutation (SHM) of antibody V regions through their modulation of the endogenous polymerase II (Pol II) transcriptional process. Extremely small amounts of Tat that could come from bystander HIV-infected cells were sufficient to promote SHM. Our data suggest HIV Tat is one missing link between HIV infection and the overall B cell genomic instability in AIDS patients. IMPORTANCE Although the introduction of antiretroviral therapy (ART) has successfully controlled primary effects of human immunodeficiency virus (HIV) infection, such as HIV proliferation and HIV-induced immune deficiency, it did not eliminate the increased susceptibility of HIV-infected patients to B cell lymphomas. We find that a secreted HIV protein, Tat, enhances the intrinsic antibody diversification mechanism by increasing the AID-induced somatic mutations at the heavy-chain variable (VH) regions in human B cells. This could contribute to the high rate of mutation in the variable regions of broadly neutralizing anti-HIV antibodies and the genomewide mutations leading to B cell malignancies in HIV carriers.

【 授权许可】

Unknown