Efficacy of Dideoxynucleosides against Human Foamy Virus and Relationship to Its Reverse Transcriptase Amino Acid Sequence and Structure

Yvon-Groussin, A.; Mugnier, Pierre; Bertin, Philippe; Grandadam, Marc; Agut, Henri; Huraux, J.M.; Cálvez, Vincent

doi:10.1128/jvi.75.15.7184-7187.2001

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…Furthermore, our results do not indicate that the residues actually involved in FV AZT resistance, are those thought previously (Yvon-Groussin et al, 2001). In particular, the residues I182, D209, V343, and K347 were modelled to be involved in PFV AZT resistance.…”

Section: Discussioncontrasting

confidence: 89%

“…Furthermore, based on homology predictions of the PFV and HIV RT enzyme structures, AZT resistance in PFV has been suggested to occur by alteration of certain residues that are known to confer AZT resistance to HIV-1 (Yvon-Groussin et al, 2001). We also wanted to investigate this possibility because experimental evidence for this theory does not exist.…”

Section: Introductionmentioning

confidence: 99%

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AZT-resistant foamy virus

et al. 2008

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Azidothymidine (AZT) is a reverse transcriptase (RT) inhibitor that efficiently blocks the replication of spumaretroviruses or foamy viruses (FVs). To more precisely elucidate the mechanism of action of the FV RT enzyme, we generated an AZT-resistant FV in cell culture. Biologically resistant virus was obtained for simian foamy virus from macaque (SFVmac), which was insensitive to AZT concentrations of 1 mM, but not for FVs derived from chimpanzees. Nucleotide sequencing revealed four non-silent mutations in the pol gene. Introduction of these mutations into an infectious molecular clone identified all changes to be required for the fully AZT-resistant phenotype of SFVmac. The alteration of individual sites showed that AZT resistance in SFVmac was likely acquired by consecutive acquisition of pol mutations in a defined order, because some alterations on their own did not result in an efficiently replicating virus, neither in the presence nor in the absence of AZT. The introduction of the mutations into the RT of the closely related prototypic FV (PFV) did not yield an AZT-resistant virus, instead they significantly impaired the viral fitness.

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Section: Discussioncontrasting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

AZT-resistant foamy virus

et al. 2008

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“…This efficient PP i -dependent excision is related to the greater polymerase activity of FV RT (PP i -mediated pyrophosphorylysis is the reverse of the polymerase reaction). However, this efficient PP i -dependent pyrophosphorylysis is not sufficient to give AZT resistance within the cell; FV is sensitive to AZT (27,31,32,34,41,42).…”

Section: Discussionmentioning

confidence: 99%

“…The basic reaction is similar to PP i pyrophosphorylysis; however, when ATP is used as the pyrophosphate donor, a dinucleoside tetraphosphate is the excision product. FV replication in tissue culture is sensitive to AZT (27,31,32,34,41,42). We measured the ability of FV RT to catalyze pyrophosphorylysis with either ATP or NaPP i as a pyrophosphate donor.…”

Section: Vol 78 2004mentioning

confidence: 99%

Characterization of the Polymerase and RNase H Activities of Human Foamy Virus Reverse Transcriptase

Boyer

Stenbak

Clark

et al. 2004

J Virol

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Foamy virus (FV) replication, while related to that of orthoretroviruses, differs at a number of steps. Several of these differences involve the reverse transcriptase (RT). There appear to be fewer RTs present in FV than in orthoretroviruses; we previously proposed that the polymerase of FV RT was more active than orthoretroviral RTs to compensate for the numerical difference. Here we present further characterization of the RT of FV. The polymerase activity of FV RT was greater than that of human immunodeficiency virus type 1 RT in a variety of assays. We also examined the RNase H activity of FV RT, and we propose that FV RT has a basic loop in the RNase H domain. Although the sequence of the basic loop of FV RT is different from the basic loop of either Moloney leukemia virus RNase H or Escherichia coli RNase H, the FV RT basic loop appears to have a similar function.Foamy viruses (FVs) are retroviruses (subfamily Spumaretrovirinae) but are in some ways distinct from typical retroviruses. The organization of the gag, pol, and env genes in the FV genome is the same as in orthoretroviruses and, like orthoretroviruses, FVs convert their single-stranded RNA genomes into integrated double-stranded DNA proviruses flanked by two long terminal repeats (LTRs), using the enzymes reverse transcriptase (RT) and integrase (IN). However, FVs have distinct features that set them apart from orthoretroviruses. Several of these differences involve either reverse transcription or the RT enzyme itself. In orthoretroviruses, such as human immunodeficiency virus type 1 (HIV-1), RT converts the single-stranded RNA genome into double-stranded DNA after the virion enters the target cell (8). In contrast, a significant portion of FV particles contain double-stranded DNA (39,41). Inhibitor studies make it clear that it is the virions with DNA genomes that infect the target cells, indicating that FV RT must be active in the cells producing the viral particles (27,41).Orthoretroviruses use a single full-length RNA transcript as the mRNA for both the gag and pol genes. Translation of the full-length RNA produces both the Gag and Gag-Pol polyproteins (8). Approximately 20 Gag proteins are produced for every Gag-Pol fusion protein (8). Gag self-assembles to form viral particles; during virus assembly, the Gag portion of the Gag-Pol fusion protein interacts with the Gag proteins. This is how the Pol proteins are incorporated into virions; the resulting virions have approximately 50 to 100 Gag-Pol polyproteins per particle (14,18,28,38). However, in an FV-infected cell, the Pol polyprotein is made independently from Gag; Pol is translated from a spliced message (13,19,39). The FV Pol polyprotein is proteolytically processed; however, it undergoes only limited processing. There is a single protease cleavage between RT and IN which releases IN and a protease-RT fusion protein (30). Protease is not cleaved from RT. The mechanism for packaging FV Pol protein into the virion appears to involve interactions of FV Pol with specific sequences in the RN...

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“…Thus, different nucleoside analogs have been analyzed for their anti-viral activity. Azidothymidine (AZT), a broadly used RT-inhibitor, is presently the only known drug effective against HFV, other dideoxynucleosides like dideoxyinosine and dideoxycytidine showed a much lower inhibitory effect for HFV compared with HIV (Rosenblum et al, 2001;Yvon-Groussin et al, 2001).…”

Section: Molecular Biology Of Foamy Virusesmentioning

confidence: 99%

Potential of Zoonotic Transmission of Non‐Primate Foamy Viruses to Humans

Bastone

Truyen

Löchelt

2003

Journal of Veterinary Medicine, Series B

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Summary 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.

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Efficacy of Dideoxynucleosides against Human Foamy Virus and Relationship to Its Reverse Transcriptase Amino Acid Sequence and Structure

Cited by 7 publications

References 30 publications

AZT-resistant foamy virus

AZT-resistant foamy virus

Characterization of the Polymerase and RNase H Activities of Human Foamy Virus Reverse Transcriptase

Potential of Zoonotic Transmission of Non‐Primate Foamy Viruses to Humans

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