Human Immunodeficiency Virus Tat Protein Aids V Region Somatic Hypermutation in Human B Cells.
mBio
; 9(2)2018 04 17.
Article
en En
| MEDLINE
| ID: mdl-29666292
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
ARN Polimerasa II
/
Región Variable de Inmunoglobulina
/
Linfocitos B
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Síndrome de Inmunodeficiencia Adquirida
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VIH-1
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Hipermutación Somática de Inmunoglobulina
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Productos del Gen tat del Virus de la Inmunodeficiencia Humana
Límite:
Humans
Idioma:
En
Revista:
MBio
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos