251. HIV-1 Viral Infectivity Factor (Vif) Alters Processive Single-stranded DNA Scanning of the Retroviral Restriction Factor APOBEC3G*
- Author
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Yuqing Feng, Robin P. Love, and Linda Chelico
- Subjects
Protein-DNA Interaction ,viruses ,Mutation, Missense ,DNA, Single-Stranded ,Enzyme Mechanisms ,APOBEC-3G Deaminase ,DNA and Chromosomes ,Biology ,Virus Replication ,Models, Biological ,Biochemistry ,chemistry.chemical_compound ,HIV Restriction Factors ,Proviruses ,immune system diseases ,Cytidine Deaminase ,vif Gene Products, Human Immunodeficiency Virus ,Humans ,Viral Immunology ,Protein–DNA interaction ,Molecular Biology ,APOBEC3G ,Virus Assembly ,Mutagenesis ,Ubiquitination ,Virion ,HIV ,virus diseases ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,Provirus ,Molecular biology ,Viral infectivity factor ,Viral Replication ,enzymes and coenzymes (carbohydrates) ,Amino Acid Substitution ,chemistry ,Viral replication ,Protein-Protein Interactions ,DNA, Viral ,Proteolysis ,HIV-1 ,DNA Deaminases ,DNA - Abstract
Background: Retroviral restriction factor APOBEC3G is inhibited from inducing mutations in HIV-1 proviral DNA in multiple ways by HIV-1 Vif. Results: Vif-mediated inhibition of APOBEC3G deoxycytidine deaminase activity is due to a change in APOBEC3G processive scanning. Conclusion: Altered processivity leads to a decrease in deoxycytidine deamination-induced mutagenesis. Significance: Vif co-encapsidation with APOBEC3G in virions may promote sublethal mutagenesis of proviral DNA., APOBEC3G is a retroviral restriction factor that can inhibit the replication of human immunodeficiency virus, type 1 (HIV-1) in the absence of the viral infectivity factor (Vif) protein. Virion-encapsidated APOBEC3G can deaminate cytosine to uracil in viral (−)DNA, which leads to hypermutation and inactivation of the provirus. APOBEC3G catalyzes these deaminations processively on single-stranded DNA using sliding and jumping movements. Vif is thought to primarily overcome APOBEC3G through an interaction that mediates APOBEC3G ubiquitination and results in its proteasomal degradation. However, Vif may also inhibit APOBEC3G mRNA translation, virion encapsidation, and deamination activity. Here we investigated the molecular mechanism of VifIIIB- and VifHXB2-mediated inhibition of APOBEC3G deamination activity. Biochemical assays using a model HIV-1 replication assay and synthetic single-stranded or partially double-stranded DNA substrates demonstrated that APOBEC3G has an altered processive mechanism in the presence of Vif. Specifically, VifHXB2 inhibited the jumping and VifIIIB inhibited the sliding movements of APOBEC3G. The absence of such an effect by Vif on degradation-resistant APOBEC3G D128K indicates that a Vif-APOBEC3G interaction mediates this effect. That the partially processive APOBEC3G was less effective at inducing mutagenesis in a model HIV-1 replication assay suggests that Vif co-encapsidation with APOBEC3G can promote sublethal mutagenesis of HIV-1 proviral DNA.
- Published
- 2013
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