Abstract
ABSTRACTLong-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.
Highlights
Long-term survivors of human immunodeficiency virus (HIV) infection have been shown to have a greatly increased incidence of B cell lymphomas
Both phenomena raise the possibility that B cells in acquired immunodeficiency syndrome (AIDS) patients are prone to exceptional genomic instability, with the mechanisms remaining to be fully illustrated
When the full-length 101-amino-acid Tat-1 protein was expressed in the Ramos somatic hypermutation (SHM) reporter cells through transduction, there was an increase in mutation reflected by approximately 2- to 2.5-fold more cells losing their fluorescence due to activation-induced deaminase (AID)-mediated mutations than the vector control (Fig. 1a; P Ͻ 0.001)
Summary
Long-term survivors of human immunodeficiency virus (HIV) infection have been shown to have a greatly increased incidence of B cell lymphomas. When the full-length 101-amino-acid (aa) Tat-1 protein was expressed in the Ramos SHM reporter cells through transduction, there was an increase in mutation reflected by approximately 2- to 2.5-fold more cells losing their fluorescence due to AID-mediated mutations than the vector control (Fig. 1a; P Ͻ 0.001).
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