Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Zielonka, Jörg; Bravo, Ignacio G.; Marino, Daniela; Conrad, Elea; Perković, Mario; Marion, Battenberg; Cichutek, Klaus; Münk, Carsten

doi:10.1128/jvi.00015-09

Cited by 41 publications

(36 citation statements)

References 102 publications

(121 reference statements)

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“…Next, we tested whether A3H haplotypes differ in their subcellular localizations. Results from previous studies addressing the subcellular localization of A3H were variable, possibly dependent on the cell type investigated and the position of the tag needed for detection (26,30,32,49). We transfected N-terminally FLAG-tagged A3H hapI-GKE and A3H hapII-RDD in HEK 293T cells and detected the FLAG signal 24 h later by confocal microscopy.…”

Section: Vol 84 2010mentioning

confidence: 99%

The Localization of APOBEC3H Variants in HIV-1 Virions Determines Their Antiviral Activity

Ooms

Majdak

Seibert

et al. 2010

J Virol

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Several members of the human APOBEC3 family of cytidine deaminases can potently restrict retroviruses such as HIV-1. The single-domain APOBEC3H (A3H) is encoded by four haplotypes, of which only A3H haplotype II-RDD (hapII-RDD) restricts HIV-1 efficiently. The goal of this study was to elucidate the mechanisms underlying the differences in antiviral activity among A3H haplotypes. The naturally occurring A3H hapI-GKE and hapII-RDD variants differ at three amino acid positions. A panel of six site-directed mutants containing combinations of the three variable residues was used to determine A3H protein expression, requirements of A3H virion incorporation, and A3H-Gag interactions. The catalytic activity of each A3H protein was assessed directly by using an Escherichia coli mutator assay. We found that the incorporation efficiencies of A3H variants into HIV-1 virions were comparable despite major differences in cellular expression. An assessment of the enzymes' catalytic activities showed that the deaminase activity of each A3H variant correlated with protein expression, suggesting similar enzymatic efficiencies. Surprisingly, virion incorporation experiments using Gag deletion mutants demonstrated that A3H haplotypes interacted with different Gag regions. A3H hapII-RDD associated with nucleocapsid in an RNA-dependent manner, whereas A3H hapI-GKE associated with the C-terminal part of matrix and the N-terminal capsid domain. Our results show that the A3H hapII-RDD interaction with nucleocapsid is critical for its antiviral activity and that the inability of A3H hapI-GKE to interact with nucleocapsid underlies its limited antiviral potential. Thus, the antiviral activity of A3H haplotypes is determined by its incorporation into the viral core, in proximity to the reverse transcription complex.

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Section: Vol 84 2010mentioning

confidence: 99%

The Localization of APOBEC3H Variants in HIV-1 Virions Determines Their Antiviral Activity

Ooms

Majdak

Seibert

et al. 2010

J Virol

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“…EIAV infection is used as a model for the study of the immunology and pathology of lentiviruses and as an efficient delivery system for gene therapy (38,39). So far, equine APOBEC is the only equine restriction factor that has been characterized (40,41). Here, we demonstrate that equine tetherin is expressed in equine macrophages, fibroblasts, and other equine cell types and is able to inhibit the release of EIAV from transfected 293T cells in vitro as potently as human tetherin.…”

Section: Discussionmentioning

confidence: 74%

Equine Tetherin Blocks Retrovirus Release and Its Activity Is Antagonized by Equine Infectious Anemia Virus Envelope Protein

Yin

et al. 2014

J Virol

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Human tetherin is a host restriction factor that inhibits replication of enveloped viruses by blocking viral release. Tetherin has an unusual topology that includes an N-terminal cytoplasmic tail, a single transmembrane domain, an extracellular domain, and a C-terminal glycosylphosphatidylinositol anchor. Tetherin is not well conserved across species, so it inhibits viral replication in a species-specific manner. Thus, studies of tetherin activities from different species provide an important tool for understanding its antiviral mechanism. Here, we report cloning of equine tetherin and characterization of its antiviral activity. Equine tetherin shares 53%, 40%, 36%, and 34% amino acid sequence identity with feline, human, simian, and murine tetherins, respectively. Like the feline tetherin, equine tetherin has a shorter N-terminal domain than human tetherin. Equine tetherin is localized on the cell surface and strongly blocks human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), and equine infectious anemia virus (EIAV) release from virus-producing cells. The antiviral activity of equine tetherin is neutralized by EIAV envelope protein, but not by the HIV-1 accessory protein Vpu, which is a human tetherin antagonist, and EIAV envelope protein does not counteract human tetherin. These results shed new light on our understanding of the species-specific tetherin antiviral mechanism.

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“…Interestingly, mouse APOBEC3 does not hypermutate viral DNA in F-MLV-, M-MLV-, or MMTV-infected cells but instead inhibits infection at an earlier replication step (21,26,29,30,(33)(34)(35). How APOBEC3-restricted viruses that lack vif-like genes, such as MLV, MMTV, and equine infectious anemia virus (36,37), counteract APOBEC3 proteins and persist in their hosts is not known.…”

mentioning

confidence: 99%

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

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Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glycoGag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivonamely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection.intrinsic immunity | trex1 | virus restriction factors

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Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Cited by 41 publications

References 102 publications

The Localization of APOBEC3H Variants in HIV-1 Virions Determines Their Antiviral Activity

The Localization of APOBEC3H Variants in HIV-1 Virions Determines Their Antiviral Activity

Equine Tetherin Blocks Retrovirus Release and Its Activity Is Antagonized by Equine Infectious Anemia Virus Envelope Protein

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

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