4.4 Article

Restriction of HIV-1 by APOBEC3G is cytidine deaminase-dependent

Journal

VIROLOGY
Volume 387, Issue 2, Pages 313-321

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2009.02.026

Keywords

HIV-1; APOBEC3G; Cytidine deaminase

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Funding

  1. NIH [T32 AI007647-09, AI058864]

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Cytidine deamination is the primary mechanism by which APOBEC3G restricts HIV-1: however, several studies have reported that APOBEC3G also inhibits virus replication via a mechanism that is independent of deamination. Using active site APOBEC3G mutants, we have re-evaluated the biological relevance of deaminase-independent APOBEC3G-mediated restriction of HIV-1. APOBEC3G proteins with Glu -> Ala mutations in AS], AS2 or AS] and AS2 were stably expressed at physiological levels in CEM-SS T cells and 293T cells and the ability of the cells to Support Delta vif HIV-1 replication was then tested. The AS2 and AS1/AS2 mutants were packaged efficiently into virions but in single-cycle or multi-cycle HIV-1 replication assays, were found to lack antiviral activity. The AS] mutant, which retained deaminase activity, maintained near wild-type antiviral function. To determine the potency of APOBEC3G antiviral activity, cell lines were established that that expressed low levels of wild-type APOBEC3G and generated virions that contained as few as 1-2 APOBEC3G molecules, Even at very low copy number, APOBEC3G caused a significant reduction in infectivity, suggesting that a single molecule of packaged APOBEC3G inactivates the virus. The high potency of APOBEC3G is consistent with a catalytic mechanism of restriction in which a single molecule can induce a string of mutations but difficult to reconcile with a deaminase-independent, non-catalytic mechanism. Analysis of the reverse transcript sequences showed that the G -> A mutations were clustered, likely reflecting the action of single APOBEC3G molecules acting processively. We conclude that cytidine deamination is the Mechanism by which APOBEC3G restricts HIV-1. (C) 2009 Elsevier Inc. All rights reserved.

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