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bioRxiv · 10.64898/2026.03.06.710055

HIV-1 Vpr counteracts TASOR restriction to promote infection prior to integration

Gibbons, J. M.·Marno, K. M.·Pade, C.·Lee, W.-Y. J.·McKnight, A.
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Abstract

HIV-1 is challenged by many intrinsic antiviral factors including APOBEC3G, Tetherin/BST-2 and SERINC5 which are overcome by viral accessory proteins Vif, Vpu and Nef respectively. HIV-1 Vpr has multiple proposed cellular targets including REAF, previously shown by us to restrict early after virus entry, but its function is incompletely understood. TASOR is a component of HuSH, an epigenetic silencing complex which inhibits expression of HIV-1 and is overcome by HIV-2/SIV Vpx. We report that TASOR, in addition to silencing integrated provirus, inhibits viral replication prior to integration during reverse transcription. TASOR impairs viral replication in primary macrophages and restriction of a primary isolate is also shown. The restriction to replication is overcome by HIV-1 Vpr which induces TASOR degradation concomitant with reverse transcription. Using Vpr mutants Q65R and F34I we show that interaction with the CRL4-DCAF1 E3 ligase and nuclear localisation are required for Vpr to mitigate TASOR. The pre and post integration mechanism of Vpr mediated TASOR mitigation is genetically segregated using cell cycle Vpr mutant R80A. TASOR depletion induces cells to accumulate in G2/M and arrested cells are more susceptible to HIV-1. Understanding the mechanistic details of pathogen-host interactions is critical for the design of effective anti-HIV/AIDS therapeutics.

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Gibbons, J. M., Marno, K. M., Pade, C., Lee, W.-Y. J., McKnight, A.. 2026-03-09. HIV-1 Vpr counteracts TASOR restriction to promote infection prior to integration. https://doi.org/10.64898/2026.03.06.710055

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