The Glycosylated Gag Protein of a Murine Leukemia Virus Inhibits the Antiretroviral Function of APOBEC3

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
Journal of Virology (Impact Factor: 4.44). 10/2010; 84(20):10933-6. DOI: 10.1128/JVI.01023-10
Source: PubMed


APOBEC proteins have evolved as innate defenses against retroviral infections. Human immunodeficiency virus (HIV) encodes
the Vif protein to evade human APOBEC3G; however, mouse retroviruses do not encode a Vif homologue, and it has not been understood
how they evade mouse APOBEC3. We report here a murine leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag)
to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild-type mice replicates
efficiently in APOBEC3 knockout mice, implying a novel role of gGag in circumventing the action of APOBEC3 in vivo.

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Available from: Leonard H Evans, Dec 17, 2013
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    • "The status of APOBEC3 as an evolutionarily-conserved retrovirus restriction factor was galvanized by a series of studies utilizing mA3 knock-out (KO) mice. Mouse mammary tumor virus, Friend retrovirus (FV) complex, Moloney murine leukemia virus (Mo-MLV), CasFrKP MLV and LP-BM5 retrovirus complex all replicated to significantly higher levels during the acute phase of infection in mA3 KO mice compared to wild-type (WT) mice (Jones et al., 2012; Kolokithas et al., 2010; Low et al., 2009; Okeoma et al., 2007; Santiago et al., 2008; Takeda et al., 2008). Furthermore, mA3 from C57BL/6 (B6) mice was shown to influence the FV-specific neutralizing antibody (NAb) response (Santiago et al., 2008; Tsuji-Kawahara et al., 2010). "
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    ABSTRACT: APOBEC1 is a cytidine deaminase involved in cholesterol metabolism that has been linked to retrovirus restriction, analogous to the evolutionarily-related APOBEC3 proteins. In particular, murine APOBEC1 was shown to inhibit Friend retrovirus (FV) in vitro, generating high levels of C-to-T and G-to-A mutations. These observations raised the possibility that FV infection might be altered in APOBEC1-null mice. To examine this question directly, we infected wild-type and APOBEC1-null mice with FV complex and evaluated acute infection levels. Surprisingly, APOBEC1-null mice exhibited similar cellular infection levels and plasma viremia relative to wild-type mice. Moreover, next-generation sequencing analyses revealed that in contrast to APOBEC3, APOBEC1 did not enhance retroviral C-to-T and G-to-A mutational frequencies in genomic DNA. Thus, APOBEC1 neither inhibited nor significantly drove the molecular evolution of FV in vivo. Our findings reinforce that not all retrovirus restriction factors characterized as potent in vitro may be functionally relevant in vivo.
    Full-text · Article · Oct 2014 · Virology
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    • "Many strains of MLV express a glycosylated form of the viral gag protein called glycogag. Glycogag mutant viruses are attenuated in wild-type, but not in APOBEC3 knockout mice [151, 152]. Glycogag forms part of the virus capsid surrounding the viral genome and is required for capsid stability [151]. "
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    ABSTRACT: Infection of cells with human immunodeficiency virus 1 (HIV-1) is controlled by restriction factors, host proteins that counteract a variety of steps in the life cycle of this lentivirus. These include SAMHD1, APOBEC3G and tetherin, which block reverse transcription, hypermutate viral DNA and prevent progeny virus release, respectively. These and other HIV-1 restriction factors are conserved and have clear orthologues in the mouse. This review summarises studies in knockout mice lacking HIV-1 restriction factors. In vivo experiments in such animals have not only validated in vitro data obtained from cultured cells, but have also revealed new findings about the biology of these proteins. Indeed, genetic ablation of HIV-1 restriction factors in the mouse has provided evidence that restriction factors control retroviruses and other viruses in vivo and has led to new insights into the mechanisms by which these proteins counteract infection. For example, in vivo experiments in knockout mice demonstrate that virus control exerted by restriction factors can shape adaptive immune responses. Moreover, the availability of animals lacking restriction factors opens the possibility to study the function of these proteins in other contexts such as autoimmunity and cancer. Further in vivo studies of more recently identified HIV-1 restriction factors in gene targeted mice are, therefore, justified.
    Preview · Article · May 2014 · Cellular and Molecular Life Sciences CMLS
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    • "However, unlike HIV-1 that encodes Vif and Vpu proteins to counteract the antiviral activity of APOBEC3 or tetherin [32,33], XMRV has not evolved means to neutralize these two cellular restriction factors. This is in contrast to other infectious murine leukemia viruses that utilize a glycosylated Gag protein to antagonize APOBEC3 [34]. In line with these findings, introducing the glycosylated Gag of moloney murine leukemia virus into XMRV facilitates XMRV replication [35]. "
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    ABSTRACT: The gammaretrovirus termed xenotropic murine leukemia virus-related virus (XMRV) was described to be isolated from prostate cancer tissue biopsies and from blood of patients suffering from chronic fatigue syndrome. However, many studies failed to detect XMRV and to verify these disease associations. Data suggesting the contamination of specimens in particular by PCR-based methods and recent reports demonstrating XMRV generation via recombination of two murine leukemia virus precursors raised serious doubts about XMRV being a genuine human pathogen. To elucidate cell tropism of XMRV, we generated replication competent XMRV reporter viruses encoding a green fluorescent protein or a secretable luciferase as tools to analyze virus infection of human cell lines or primary human cells. Transfection of proviral DNAs into LNCaP prostate cancer cells resulted in readily detectably reporter gene expression and production of progeny virus. Inoculation of known XMRV susceptible target cells revealed that these virions were infectious and expressed the reporter gene, allowing for a fast and highly sensitive quantification of XMRV infection. Both reporter viruses were capable of establishing a spreading infection in LNCaP and Raji B cells and could be easily passaged. However, after inoculation of primary human blood cells such as CD4 T cells, macrophages or dendritic cells, infection rates were very low, and a spreading infection was never established. In line with these results we found that supernatants derived from these XMRV infected primary cell types did not contain infectious virus. Thus, although XMRV efficiently replicated in some human cell lines, all tested primary cells were largely refractory to XMRV infection and did not support viral spread. Our results provide further evidence that XMRV is not a human pathogen.
    Full-text · Article · Sep 2013 · PLoS ONE
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