Comparative analysis of the alphavirus-based vectors expressing Rift Valley fever virus glycoproteins

Gorchakov, Rodion; Volkova, Eugenia; Yun, Nadezda; Petrakova, Olga; Linde, Nathaniel S.; Paessler, Slobodan; Frolova, Elena I.; Frolov, Ilya

doi:10.1016/j.virol.2007.04.014

Cited by 42 publications

(36 citation statements)

References 47 publications

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“…In this study, we performed extensive mutational analyses aimed at identifying the function of each element in virus and RNA replication. Previously published data unambiguously demonstrated that alphavirus structural proteins are dispensable for the replication of the viral genome and the transcription of subgenomic RNA (10,28,37). This study was based on the construction, selection, and analysis of numerous virus variants having modified 5ЈUTRs, and such modifications could make VEEV, even its attenuated variant TC-83, more pathogenic (17).…”

Section: Resultsmentioning

confidence: 96%

Structural and Functional Elements of the Promoter Encoded by the 5′ Untranslated Region of the Venezuelan Equine Encephalitis Virus Genome

Kulasegaran‐Shylini

Atasheva

Gorenstein

et al. 2009

J Virol

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Venezuelan equine encephalitis virus (VEEV) is one of the most pathogenic members of the Alphavirus genus in the Togaviridae family. The pathogenesis of this virus depends strongly on the sequences of the structural proteins and on the mutations in the RNA promoter encoded by the 5 untranslated region (5UTR) of the viral genome. In this study, we performed a detailed investigation of the structural and functional elements of the 5-terminal promoter and analyzed the effect of multiple mutations introduced into the VEEV 5UTR on virus and RNA replication. The results of this study demonstrate that RNA replication is determined by two synergistically functioning RNA elements. One of them is a very 5-terminal AU dinucleotide, which is not involved in the stable RNA secondary structure, and the second is a short, G-C-rich RNA stem. An increase or decrease in the stem's stability has deleterious effects on virus and RNA replication. In response to mutations in these RNA elements, VEEV replicative machinery was capable of developing new, compensatory sequences in the 5UTR either containing 5-terminal AUG or AU repeats or leading to the formation of new, heterologous stem-loops. Analysis of the numerous compensatory mutations suggested that at least two different mechanisms are involved in their generation. Some of the modifications introduced into the 5 terminus of the viral genome led to an accumulation of the mutations in the VEEV nsPs, which suggested to us that there is a direct involvement of these proteins in promoter recognition. Furthermore, our data provide new evidence that the 3 terminus of the negative-strand viral genome in the double-stranded RNA replicative intermediate is represented by a single-stranded RNA. Both the overall folding and the sequence determine its efficient function as a promoter for VEEV positive-strand RNA genome synthesis.

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Section: Resultsmentioning

confidence: 96%

Structural and Functional Elements of the Promoter Encoded by the 5′ Untranslated Region of the Venezuelan Equine Encephalitis Virus Genome

Kulasegaran‐Shylini

Atasheva

Gorenstein

et al. 2009

J Virol

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“…Another possibility is to package PIV genomes into infectious viral particles. Alphavirus packaging systems have been developed by numerous research teams and are widely applied (38)(39)(40)(41)(42). Usually packaging is achieved by cotransfecting cells with an in vitro-synthesized defective viral genome and helper RNAs that lack some or all of the nonstructural genes but encode one or more structural proteins under the control of the subgenomic promoter or internal ribosome entry sequence (IRES) (36,43).…”

Section: Discussionmentioning

confidence: 99%

Pseudoinfectious Venezuelan Equine Encephalitis Virus: a New Means of Alphavirus Attenuation

Atasheva

Kim

Akhrymuk

et al. 2013

J Virol

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bVenezuelan equine encephalitis virus (VEEV) is a reemerging virus that causes a severe and often fatal disease in equids and humans. In spite of a continuous public health threat, to date, no vaccines or antiviral drugs have been developed for human use. Experimental vaccines demonstrate either poor efficiency or severe adverse effects. In this study, we developed a new strategy of alphavirus modification aimed at making these viruses capable of replication and efficient induction of the immune response without causing a progressive infection, which might lead to disease development. To achieve this, we developed a pseudoinfectious virus (PIV) version of VEEV. VEE PIV mimics natural viral infection in that it efficiently replicates its genome, expresses all of the viral structural proteins, and releases viral particles at levels similar to those found in wild-type VEEV-infected cells. However, the mutations introduced into the capsid protein make this protein almost incapable of packaging the PIV genome, and most of the released virions lack genetic material and do not produce a spreading infection. Thus, VEE PIV mimics viral infection in terms of antigen production but is safer due to its inability to incorporate the viral genome into released virions. These genome-free virions are referred to as virus-like particles (VLPs). Importantly, the capsid-specific mutations introduced make the PIV a very strong inducer of the innate immune response and add self-adjuvant characteristics to the designed virus. This unique strategy of virus modification can be applied for vaccine development against other alphaviruses.

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“…Unlike other recombinant RVFV vaccines, such as live-attenuated RVFV or alphavirus replicons (4,19,44), the CAdVax-RVF vaccine does not replicate inside the body and therefore has an increased level of safety inherent in its design. Increased vaccine safety is a major issue given the dangerous side effects of the current veterinary RVFV vaccine, which causes spontaneous abortions in cattle (6) and birth defects in sheep (23).…”

Section: Discussionmentioning

confidence: 99%

“…While the use of rLSDV-RVFV is feasible only as a potential veterinary vaccine against RVFV and sheeppox virus, the result supports the use of RVFV glycoproteins for a vaccine. Expression of the Gc protein alone using a Venezuelan equine encephalitis virus (VEEV) replicon provided protection against RVFV challenge in mice following a single injection (19). Mice were also protected from challenge following immunization with a VEEV expressing a 318-aminoacid fragment of Gc fused to the E2 glycoprotein of the vector.…”

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confidence: 99%

A Complex Adenovirus-Vectored Vaccine against Rift Valley Fever Virus Protects Mice against Lethal Infection in the Presence of Preexisting Vector Immunity

Holman¹,

Penn-Nicholson²,

Wang³

et al. 2009

Clin Vaccine Immunol

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Rift Valley fever virus (RVFV) has been cited as a potential biological-weapon threat due to the serious and fatal disease it causes in humans and animals and the fact that this mosquito-borne virus can be lethal in an aerosolized form. Current human and veterinary vaccines against RVFV, however, are outdated, inefficient, and unsafe. We have incorporated the RVFV glycoprotein genes into a nonreplicating complex adenovirus (CAdVax) vector platform to develop a novel RVFV vaccine. Mice vaccinated with the CAdVax-based vaccine produced potent humoral immune responses and were protected against lethal RVFV infection. Additionally, protection was elicited in mice despite preexisting immunity to the adenovirus vector.

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Comparative analysis of the alphavirus-based vectors expressing Rift Valley fever virus glycoproteins

Cited by 42 publications

References 47 publications

Structural and Functional Elements of the Promoter Encoded by the 5′ Untranslated Region of the Venezuelan Equine Encephalitis Virus Genome

Structural and Functional Elements of the Promoter Encoded by the 5′ Untranslated Region of the Venezuelan Equine Encephalitis Virus Genome

Pseudoinfectious Venezuelan Equine Encephalitis Virus: a New Means of Alphavirus Attenuation

A Complex Adenovirus-Vectored Vaccine against Rift Valley Fever Virus Protects Mice against Lethal Infection in the Presence of Preexisting Vector Immunity

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