Vpu modulates DNA repair to suppress innate sensing and hyper-integration of HIV-1.

Nature Microbiology
Meta VolcicFrank Kirchhoff

Abstract

To avoid innate sensing and immune control, human immunodeficiency virus type 1 (HIV-1) has to prevent the accumulation of viral complementary DNA species. Here, we show that the late HIV-1 accessory protein Vpu hijacks DNA repair mechanisms to promote degradation of nuclear viral cDNA in cells that are already productively infected. Vpu achieves this by interacting with RanBP2-RanGAP1*SUMO1-Ubc9 SUMO E3-ligase complexes at the nuclear pore to reprogramme promyelocytic leukaemia protein nuclear bodies and reduce SUMOylation of Bloom syndrome protein, unleashing end degradation of viral cDNA. Concomitantly, Vpu inhibits RAD52-mediated homologous repair of viral cDNA, preventing the generation of dead-end circular forms of single copies of the long terminal repeat and permitting sustained nucleolytic attack. Our results identify Vpu as a key modulator of the DNA repair machinery. We show that Bloom syndrome protein eliminates nuclear HIV-1 cDNA and thereby suppresses immune sensing and proviral hyper-integration. Therapeutic targeting of DNA repair may facilitate the induction of antiviral immunity and suppress proviral integration replenishing latent HIV reservoirs.

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Citations

Jul 6, 2021·Frontiers in Oncology·Julia EberleLisa Wiesmüller
Jul 30, 2021·Nature Communications·Caterina Prelli BozzoFrank Kirchhoff

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Datasets Mentioned

BETA
GMO8505

Methods Mentioned

BETA
transfection
PCR
FACS
immunoprecipitation
immunoprecipitations
confocal microscopy
nuclear translocation
FCS
flow cytometry
protein assay

Software Mentioned

Prism
ImageJ
GraphPad
Vpu
LSM

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