Human immunodeficiency virus tat protein aids V region somatic hypermutation in human B cells

Xiaohua Wang, Zhi Duan, Guojun Yu, Manxia Fan, Matthew D. Scharff

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere02315-17
JournalmBio
Volume9
Issue number2
DOIs
StatePublished - Mar 1 2018

Fingerprint

tat Gene Products
Human Immunodeficiency Virus Proteins
B-Lymphocytes
HIV
Virus Diseases
Antibodies
Genomic Instability
B-Cell Lymphoma
INDEL Mutation
Mutation
Mutation Rate

Keywords

  • AID
  • AIDS
  • B cell
  • HIV
  • Somatic hypermutation
  • Tat

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Human immunodeficiency virus tat protein aids V region somatic hypermutation in human B cells. / Wang, Xiaohua; Duan, Zhi; Yu, Guojun; Fan, Manxia; Scharff, Matthew D.

In: mBio, Vol. 9, No. 2, e02315-17, 01.03.2018.

Research output: Contribution to journalArticle

Wang, Xiaohua ; Duan, Zhi ; Yu, Guojun ; Fan, Manxia ; Scharff, Matthew D. / Human immunodeficiency virus tat protein aids V region somatic hypermutation in human B cells. In: mBio. 2018 ; Vol. 9, No. 2.
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