The 3′ Untranslated Region of the Andes Hantavirus Small mRNA Functionally Replaces the Poly(A) Tail and Stimulates Cap-Dependent Translation Initiation from the Viral mRNA

Vera-Otárola, Jorge; Soto-Rifo, Ricardo; Ricci, Emiliano P.; Ohlmann, Théophile; Darlix, Jean‐Luc; López-Lastra, Marcelo

doi:10.1128/jvi.01270-10

Cited by 16 publications

(37 citation statements)

References 49 publications

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“…Both S-and L-IGRs act as bona fide transcriptional termination signals that generate nonpolyadenylated viral mRNA species whose 3= ends have been mapped to multiple sites within the distal site of the IGR (21,24). As reported for bunyavirus (40,41), which also has nonpolyadenylated mRNAs, the 3= UTR of arenavirus mRNA may be able to play a role as a surrogate for a poly(A) tail that recruits cellular components that promote the interaction between the 5= cap and 3= end of the mRNA to facilitate repetitive use of a released ribosome for efficient translation. Differences in sequence and structure at the 3= UTR might have contributed to the efficiency of formation of translational complexes and influenced virus protein expression.…”

Section: Discussionmentioning

confidence: 97%

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

Iwasaki

Ngo

Cubitt

et al. 2015

J Virol

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Hemorrhagic fever arenaviruses (HFA) pose important public health problems in regions where they are endemic. Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, causing a large number of Lassa fever cases associated with high morbidity and mortality. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. The Mopeia virus (MOPV)/LASV reassortant (ML29) is a LASV candidate live-attenuated vaccine (LAV) that has shown promising results in animal models. Nevertheless, the mechanism of ML29 attenuation remains unknown, which raises concerns about the phenotypic stability of ML29 in response to additional mutations. Development of LAVs based on well-defined molecular mechanisms of attenuation will represent a major step in combatting HFA. We used the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to develop a general molecular strategy for arenavirus attenuation. Our approach involved replacement of the noncoding intergenic region (IGR) of the L genome segment with the IGR of the S genome segment to generate a recombinant LCMV, rLCMV(IGR/S-S), that was highly attenuated in vivo but induced protection against a lethal challenge with wild-type LCMV. Attenuation of rLCMV(IGR/S-S) was associated with a stable reorganization of the control of viral gene expression. This strategy can facilitate the rapid development of LAVs with the antigenic composition of the parental HFA and a mechanism of attenuation that minimizes concerns about increased virulence that could be caused by genetic changes in the LAV. IMPORTANCEHemorrhagic fever arenaviruses (HFA) cause high morbidity and mortality, and pose important public health problems in the regions where they are endemic. Implementation of live-attenuated vaccines (LAV) will represent a major step in combatting HFA. Here we have used the prototypic arenavirus LCMV to document a general molecular strategy for arenavirus attenuation that can facilitate the rapid development of safe and effective, as well as stable, LAV to combat HFA. Hemorrhagic fever arenaviruses (HFA) pose important public health problems in the regions where they are endemic (1-3). Thus, Lassa virus (LASV) infects several hundred thousand individuals yearly in West Africa, resulting in a high number of Lassa fever (LF) cases associated with high morbidity and significant mortality (4). Notably, increased traveling has led to the importation of LF cases into metropolitan areas around the globe where the virus is not endemic (5, 6). Moreover, regions of LASV endemicity are expanding (4), and the association of the recently identified arenavirus Lujo with a recent outbreak of HF in southern Africa (7,8) has raised concerns about the emergence of novel HFA. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis vi...

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Section: Discussionmentioning

confidence: 97%

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

Iwasaki

Ngo

Cubitt

et al. 2015

J Virol

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“…Additionally, UTRs of the Bunyaviridae family are presumed to contain signals for encapsidation by the viral NP to form RNPs, signals for regulation of transcription and replication and signals for packaging the RNPs into virions (Kohl et al, 2006;Mir and Panganiban, 2010;Vera-Otarola et al, 2010). Moreover, it was reported that viral UTRs also participated in host cell regulation networks (Flick et al, 2002;Habjan et al, 2008;Sriskanda et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Mini-genome rescue of Crimean-Congo hemorrhagic fever virus and research into the evolutionary patterns of its untranslated regions

et al. 2013

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“…5Ј IRES activity can be enhanced by interaction with specific elements in 3Ј UTRs, leading to template circularization similar to that of host mRNAs (20,21,51,55,63). Protein-dependent cyclization involving the 3Ј poly(A) tail and 5Ј IRES has been characterized for picornaviruses (11) and Tobacco etch potyvirus, a member of the poliovirus superfamily (41,48).…”

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confidence: 99%

Ribosome Binding to a 5′ Translational Enhancer Is Altered in the Presence of the 3′ Untranslated Region in Cap-Independent Translation of Turnip Crinkle Virus

Stupina

Yuan

Meškauskas

et al. 2011

J Virol

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Plus-strand RNA viruses without 5 caps require noncanonical mechanisms for ribosome recruitment. A translational enhancer in the 3 untranslated region (UTR) of Turnip crinkle virus (TCV) contains an internal T-shaped structure (TSS) that binds to 60S ribosomal subunits. We now report that the 63-nucleotide (nt) 5 UTR of TCV contains a 19-nt pyrimidine-rich element near the initiation codon that supports translation of an internal open reading frame (ORF) independent of upstream 5 UTR sequences. Addition of 80S ribosomes to the 5 UTR reduced the flexibility of the polypyrimidine residues and generated a toeprint consistent with binding to this region. Binding of salt-washed 40S ribosomal subunits was reduced 6-fold when the pyrimidinerich sequence was mutated. 40S subunit binding generated the same toeprint as 80S ribosomes but also additional ones near the 5 end. Generation of out-of-frame AUGs upstream of the polypyrimidine region reduced translation, which suggests that 5-terminal entry of 40S subunits is followed by scanning and that the polypyrimidine region is needed for an alternative function that requires ribosome binding. No evidence for RNA-RNA interactions between 5 and 3 sequences was found, suggesting that TCV utilizes an alternative means for circularizing its genome. Combining 5 and 3 UTR fragments in vitro had no discernible effect on the structures of the RNAs. In contrast, when 80S ribosomes were added to both fragments, structural changes were found in the 5 UTR polypyrimidine tract that were not evident when ribosomes interacted with the individual fragments. This suggests that ribosomes can promote an interaction between the 5 and 3 UTRs of TCV.

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The 3′ Untranslated Region of the Andes Hantavirus Small mRNA Functionally Replaces the Poly(A) Tail and Stimulates Cap-Dependent Translation Initiation from the Viral mRNA

Cited by 16 publications

References 49 publications

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

General Molecular Strategy for Development of Arenavirus Live-Attenuated Vaccines

Mini-genome rescue of Crimean-Congo hemorrhagic fever virus and research into the evolutionary patterns of its untranslated regions

Ribosome Binding to a 5′ Translational Enhancer Is Altered in the Presence of the 3′ Untranslated Region in Cap-Independent Translation of Turnip Crinkle Virus

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