Cell Host & Microbe
Volume 14, Issue 4, 16 October 2013, Pages 411-421
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Article
HIV-1 Vif Adaptation to Human APOBEC3H Haplotypes

https://doi.org/10.1016/j.chom.2013.09.006Get rights and content
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Highlights

  • Patients with active A3H more often have an A3H-resistant HIV

  • Endogenously expressed A3H restricts HIV replication in primary cells

  • A3H restriction of HIV in primary cells correlates with proviral editing

  • The Vif amino acid at position 39 determines degradation efficiency of A3H

Summary

Several human APOBEC3 deaminases can inhibit HIV-1 replication in vitro. HIV-1 Vif counteracts this restriction by targeting APOBEC3 for proteasomal degradation. Human APOBEC3H (A3H) is highly polymorphic, with natural variants differing considerably in anti-HIV-1 activity in vitro. To examine HIV-1 adaptation to variation in A3H activity in a natural infection context, we determined the A3H haplotypes and Vif sequences from 76 recently infected HIV-1 patients. We detected A3H-specific Vif changes suggesting viral adaptation. The patient-derived Vif sequences were used to engineer viruses that specifically differed in their ability to counteract A3H. Replication of these Vif-variant viruses in primary T cells naturally expressing active or inactive A3H haplotypes showed that endogenously expressed A3H restricts HIV-1 replication. Proviral DNA from A3H-restricted viruses showed high levels of G-to-A mutations in an A3H-specific GA dinucleotide context. Taken together, our data validate A3H expressed at endogenous levels as a bona fide HIV-1 restriction factor.

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These authors contributed equally to this work