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  • 1
    Keywords: COMBINATION ; Germany ; INHIBITION ; SITE ; PROTEIN ; RELEASE ; MECHANISM ; DOMAIN ; BIOLOGY ; MEMBER ; MEMBERS ; MOLECULAR-BIOLOGY ; SEQUENCE ; SEQUENCES ; SIGNAL ; MATURATION ; ACID ; CLEAVAGE ; GLYCOPROTEIN ; virus ; RETROVIRUSES ; COMPONENT ; PEPTIDES ; REPLICATION ; INTERACTS ; CLEAVAGE SITE ; foamy virus ; GAG ; INFECTIVITY ; protease ; MALDI-MS ; molecular biology ; FEATURES ; RESIDUES ; VIRIONS ; 2-DIMENSIONAL ELECTROPHORESIS ; ENVELOPE GLYCOPROTEINS ; RESCUE ; TERMINAL GAG DOMAIN
    Abstract: The molecular biology of spuma or foamy retroviruses is different from that of the other members of the Retroviridae. Among the distinguishing features, the N-terminal domain of the foamy virus Env glycoprotein, the 16-kDa Env leader protein Elp, is a component of released, infectious virions and is required for particle budding. The transmembrane protein Elp specifically interacts with N-terminal Gag sequences during morphogenesis. In this study, we investigate the mechanism of Elp release from the Env precursor protein. By a combination of genetic, biochemical, and biophysical methods, we show that the feline foamy virus (FFV) Elp is released by a cellular furin-like protease, most likely furin itself, generating an Elp protein consisting of 127 amino acid residues. The cleavage site fully conforms to the rules for an optimal furin site. Proteolytic processing at the furin cleavage site is required for full infectivity of FFV. However, utilization of other furin proteases and/or cleavage at a suboptimal signal peptidase cleavage site can partially rescue virus viability. In addition, we show that FFV Elp carries an N-linked oligosaccharide that is not conserved among the known foamy viruses
    Type of Publication: Journal article published
    PubMed ID: 15564468
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  • 2
    Keywords: CELLS ; EXPRESSION ; Germany ; CLONING ; GENE ; PROTEIN ; PROTEINS ; transcription ; RELEASE ; DNA ; FAMILY ; DOMAIN ; CARCINOGENESIS ; CONTRAST ; PARTICLES ; virus ; DEGRADATION ; REPLICATION ; ANTIVIRAL ACTIVITY ; CONSTRUCTION ; IMMUNODEFICIENCY-VIRUS ; RE ; spumaretrovirus ; zoonosis ; cytidine deamination ; HIV-1 VIF ; HYPERMUTATION ; restriction factor ; virion infectivity factor
    Abstract: Genome hypermutation of different orthoretroviruses by cellular cytidine deaminases of the APOBEC3 family during reverse transcription has recently been observed. Lentiviruses like HIV-1 have acquired proteins preventing genome editing in the newly infected cell. Here we show that feline foamy virus (FFV), a typical member of the foamy retrovirus subfamily Spumaretrovirinae, is also refractory to genome deamination. APOBEC3-like FFV genome editing in APOBEC3-positive feline CRFK cells only occurs when the accessory FFV Bet protein is functionally inactivated. Editing of bet-deficient FFV genomes is paralleled by a strong decrease in FFV titer. In contrast to lentiviruses, cytidine deamination already takes place in APOBEC3-positive FFV-producing cells, because edited proviral DNA genomes are consistently present in released particles. By cloning the feline APOBEC3 orthologue, we found that its homology to the second domain of human APOBEC3F is 48%. Expression of feline APOBEC3 in APOBEC3-negative human 293T cells reproduced the effects seen in homologous CRFK cells: Bet-deficient FFV displayed severely reduced titers, high-level genome editing, reduced particle release, and suppressed Gag processing. Although WT Bet efficiently preserved FFV infectivity and genome integrity, it sustained particle release and Gag processing only when fe3 was moderately expressed. Similar to lentiviral Vif proteins, FFV Bet specifically bound feline APOBEC3. In particles from Bet-deficient FFV, feline APOBEC3 was clearly present, whereas its foamy viral antagonist Bet was undetectable in purified WT particles. This is the first report that, in addition to lentiviruses, the foamy viruses also developed APOBEC3-counteracting proteins
    Type of Publication: Journal article published
    PubMed ID: 15911774
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  • 3
    Keywords: GENE ; PROTEIN ; BINDING ; TRANSACTIVATOR ; GLYCOPROTEIN ; RETROVIRUSES ; VECTORS ; LOCALIZATION ; REPLICATION ; foamy virus ; GAG ; CONSTRUCTION ; Env-Gag interaction ; INFECTIVITY ; POL POLYPROTEIN
    Abstract: Previous studies have shown that foamy virus (FV) particle budding, especially the involvement of the viral Env glycoprotein, is different from that of other (ortho) retroviruses: the N-terminal Env leader protein Elp is a constituent of released FV particles. A defined sequence in Elp required for particle budding binds to the MA domain of Gag. To extend these findings, we show that feline FV Elp is a membrane-anchored protein with the N-terminus located inside the particle. Thus, the internal/cytoplasmic domain of Elp has the correct topology for interacting with Gag during budding. In addition to Elp, an Elp-related protein of about 9 kDa was shown to be virion associated and is probably generated by cellular signal peptidases. Besides the function of Elp binding, the N-terminal domain of Gag was shown to be required for proper localization of feline FV Gag to the cytoplasm and the perinuclear/nuclear region. (C) 2003 Elsevier Science (USA). All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12781711
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  • 4
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; RISK ; GENE ; GENES ; GENOME ; PROTEIN ; TRANSDUCTION ; recombination ; animals ; SEQUENCE ; SEQUENCES ; virus ; DELETION ; VECTORS ; DESIGN ; PROMOTER ; CELL-LINE ; FLUORESCENCE ; GENE-THERAPY ; RETROVIRAL VECTORS ; VIRAL VECTORS ; MURINE LEUKEMIA-VIRUS ; ENHANCER ; foamy virus,self-inactivating vector,retrovirus,replication-competent revertant,bio-safety ; PACKAGING CONSTRUCTS
    Abstract: In this study, self-inactivating (SIN) retroviral vectors based on feline foamy virus (FFV) were constructed and analysed. The FFV SIN vectors were devoid of the core FFV long terminal repeat promoter plus upstream sequences but contained all structural and regulatory genes. This design allowed sensitive detection of replication-competent revertants (RCRs). The FFV SIN vectors efficiently transduced the green fluorescence protein into recipient cells. However, RCRs appeared after serial passages of transduced cells. In all RCR clones analysed, parts of the heterologous cytomegalovirus immediate early promoter, originally driving expression of the FFV vector genome, were taken up to restore the deleted SIN promoter function required for replication competence. The RCRs were strongly reduced in replication capacity compared with the parental replication-competent vectors containing the FFV promoter. In all RCR genomes analysed, the uptake of the heterologous promoter was accompanied by deletion of almost the complete marker gene. Although the RCRs described in this study may not have the capacity to spread in humans and animals, they may pose a theoretical risk, for instance during transduction of haematopoietic stem cells. Thus, FV-based SIN vectors require additional genetic modifications in order to avoid RCRs
    Type of Publication: Journal article published
    PubMed ID: 14973540
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  • 5
    Keywords: EXPRESSION ; Germany ; TOOL ; SITE ; GENE ; GENOME ; PROTEIN ; PROTEINS ; RNA ; gene therapy ; gene transfer ; GENE-TRANSFER ; MARKER ; SEQUENCE ; SEQUENCES ; virus ; IDENTIFICATION ; VECTOR ; ELEMENTS ; REGION ; DELIVERY ; transactivation ; foamy virus ; GAG ; RETROVIRAL VECTORS ; CONSTRUCTION ; GENE DELIVERY ; POL ; ENV LEADER PROTEIN ; REPLICATION STRATEGY ; cis-acting element ; packaging ; spumavirus
    Abstract: Retroviral vectors derived from foamy or spumaretroviruses are considered promising tools for targeted gene delivery and vaccination purposes. In order to fully exploit this potential, we identified essential cis-acting sequences on the feline foamy virus (FFV) genome by constructing and analyzing a series of FFV-based replication-deficient vector genomes. Cis-acting sequences essentially required for marker gene transfer were found to be localized at two sites on the FFV genome: (i) in the 5'-untranslated region and close to the gag ATG and (ii) in the central part of the pol gene. The presence of two cis-acting sequences and their relative location on the FFV genome are similar but not identical to the functionally corresponding elements described for simian and primate foamy viruses. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16443252
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  • 6
    Keywords: Germany ; human ; POPULATION ; RISK ; GENE ; PROTEIN ; MOLECULAR CHARACTERIZATION ; INFECTION ; CARE ; CATS ; GAG PRECURSOR ; GRAVES-DISEASE ; HEALTH ; HOST RANGE ; HUMANS ; lifestyle ; RETROVIRUSES ; REVERSE-TRANSCRIPTASE ; VECTORS
    Abstract: The zoonotic introduction of an animal pathogen into the human population and the subsequent extension or alteration of its host range leading to the successful maintenance of the corresponding pathogen by human-to-human transmission pose a serious risk for world-wide health care. Such a scenario occurred for instance by the introduction of simian immunodeficiency viruses into the human population resulting in the human immunodeficiency viruses (HIV) and the subsequent AIDS pandemic or the proposed recent host range switch of the SARS coronavirus from a presently unknown animal species to humans. The occurrence of zoonotic transmissions of animal viruses to humans is a permanent threat to human health and is even increased by changes in the human lifestyle. In this review, the potential of the zoonotic transmission of bovine, feline and equine foamy retroviruses will be discussed in the light of well-documented cases of zoonotic transmissions of different simian foamy viruses to humans
    Type of Publication: Journal article published
    PubMed ID: 14633194
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  • 7
    Keywords: Germany ; human ; POPULATION ; GENE ; PROTEIN ; MOLECULAR CHARACTERIZATION ; INFECTION ; animals ; CATS ; GRAVES-DISEASE ; RETROVIRUSES ; VECTORS ; REPLICATION ; INFECTIONS ; foamy virus ; GAG ; pathogen ; PATHOGENS ; spumaretrovirus ; zoonosis
    Abstract: Human infections by pathogens originating from animals is a permanent threat. In particular the potency of transmition within the human population is the prerequisite for an epidemic or pandemic distribution of the new pathogen. This scenario has happened in the past on several independent occasions with the simian immunodeficiency viruses, which led to the HIV (AIDS) pandemic. The same appeared to have happened with the SARS coronavirus epidemic, although the authentic animal host has not yet been defined. This review summarizes well documented cases of transmission of various simian foamyviruses to man and discusses the zoonotic potential of nonhuman foamyvirus from cats, cattle and horses
    Type of Publication: Journal article published
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  • 8
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; THERAPY ; EXPOSURE ; LONG-TERM ; GENE ; GENE-EXPRESSION ; gene therapy ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; MARKER ; BIOLOGY ; TARGET ; virus ; DELETION ; VECTOR ; PROMOTER ; NUMBER ; PROMOTERS ; genetics ; EFFICIENT ; REPLICATION ; GENE-THERAPY ; RETROVIRAL VECTORS ; CONSTRUCTION ; heredity ; FELINE FOAMY VIRUS ; ARRAY ; TERMINAL GAG DOMAIN ; PROFILES ; ENV LEADER PROTEIN ; UBIQUITIN ; RETROVIRUS ; ACCESSORY BET PROTEIN ; biosafety ; deficient vector ; lacZ ; NOD/SCID-REPOPULATING CELLS ; SIN vector ; UBIQUITIN-C
    Abstract: As serious side effects affected recent virus-mediated gene transfer studies, novel vectors with improved safety profiles are urgently needed. In the present study, replication-deficient retroviral vectors based on feline foamy virus (FFV) were constructed and analyzed. The novel FFV vectors are devoid of almost the complete env gene plus the internal promoter - accessory bel gene cassette including the gene for the viral transcriptional transactivator Bel1/Tas. In these Bel1/Tas-independent vectors, expression of the lacZ (beta-galactosidase) marker gene is directed by the heterologous, constitutively active human ubiquitin C promoter (ubl). Env-transcomplemented vectors have unconcentrated titers of more than 10(5) transducing units/ml. The vectors allow efficient transduction of a broad array of diverse target cells, which can be increased by repeated vector exposure. However, the number of lacZ marker gene expressing cells decreased slightly upon serial passages of the transduced cells. Vectors carrying a self-inactivating (SIN) deletion of the TATA box and most parts of the viral promoter were not rescued by wt FFV whereas those with the intact or a partially deleted promoter were readily reactivated. This finding indicates that the viral promoters are in fact non-functional, pointing to a highly advantageous safety profile of these new FFV-ubi-lacZ-SIN vectors
    Type of Publication: Journal article published
    PubMed ID: 17203107
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