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

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.

• Authors: Xiaohua Wang, Zhi Duan, Guojun Yu, Manxia Fan, Matthew D Scharff
• Journal: mBio (mBio) Vol. 9 Issue 2 (04 17 2018) ISSN: 2150-7511 [Electronic] United States
• PMID: 29666292 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Wang et al.

Chemical References

• Immunoglobulin Variable Region
• tat Gene Products, Human Immunodeficiency Virus
• RNA Polymerase II

Topics

• Acquired Immunodeficiency Syndrome (pathology)
• B-Lymphocytes (immunology)
• HIV-1 (immunology)
• Humans
• Immunoglobulin Variable Region (genetics)
• RNA Polymerase II (metabolism)
• Somatic Hypermutation, Immunoglobulin
• tat Gene Products, Human Immunodeficiency Virus (metabolism)