Alphavirus replicon particles acting as adjuvants promote CD8+ T cell responses to co-delivered antigen

Thompson, Jeff. E.; Whitmore, Alan C.; Staats, Herman F.; Johnston, Robert E.

doi:10.1016/j.vaccine.2008.05.046

Cited by 35 publications

(36 citation statements)

References 52 publications

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“…Potency associated with the VRP-based vaccines may be partially attributed to the propensity of VRPs to infect antigen-presenting cells, in particular, dendritic cells (43). Natural adjuvant properties of VRPs are known to promote antigen-specific T cell immunity and regulate a balanced antigen specific antibody response, which may also contribute to the potency of the VRP vaccine platform (44). Differences in genomic nucleotide (37 to 41% homologous) and amino acid (34 to 43% homologous) sequence homology among ebolaviruses have made cross-species protection difficult.…”

Section: Discussionmentioning

confidence: 99%

Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus

Herbert

Kuehne

Barth

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 99%

Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus

Herbert

Kuehne

Barth

et al. 2013

J Virol

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“…An additional benefit of self-replicating PIV genome delivery instead of the use of standard RNA polymerase II-dependent cassettes is the ability of PIV RNA replication to efficiently induce proinflammatory cytokines, and thus to serve as an adjuvant (30,47).…”

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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“…(ii) Capsid proteins of the Old World alphaviruses, in contrast to the New World alphavirus-specific capsids, do not block nuclear cytoplasmic trafficking and cause no inhibition of cellular transcription (24,26). (iii) VEEV replicons and VEEV variants with certain mutations in capsid protein induce high levels of cytokines and have been proposed as efficient biological adjuvants (15,(51)(52)(53)(54). (iv) Alphavirus structural proteins (capsid, E2, and E1) efficiently package RNA genomes, in which all of the nonstructural genes and cis-acting promoter elements are derived from heterologous alphaviruses (7,18,31,40,56,57).…”

Section: Discussionmentioning

confidence: 99%

Design of Chimeric Alphaviruses with a Programmed, Attenuated, Cell Type-Restricted Phenotype

Kim

Atasheva

Foy

et al. 2011

J Virol

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The Alphavirus genus in the Togaviridae family contains a number of human and animal pathogens. The importance of alphaviruses has been strongly underappreciated; however, epidemics of chikungunya virus (CHIKV), causing millions of cases of severe and often persistent arthritis in the Indian subcontinent, have raised their profile in recent years. In spite of a continuous public health threat, to date no licensed vaccines have been developed for alphavirus infections. In this study, we have applied an accumulated knowledge about the mechanism of alphavirus replication and protein function in virus-host interactions to introduce a new approach in designing attenuated alphaviruses. These variants were constructed from genes derived from different, geographically isolated viruses. The resulting viable variants encoded CHIKV envelope and, in contrast to naturally circulating viruses, lacked the important contributors to viral pathogenesis: genes encoding proteins functioning in inhibition of cellular transcription and downregulation of the cellular antiviral response. To make these viruses incapable of transmission by mosquito vectors and to differentially regulate expression of viral structural proteins, their replication was made dependent on the internal ribosome entry sites, derived from other positive-polarity RNA (RNA ؉ ) viruses. The rational design of the genomes was complemented by selection procedures, which adapted viruses to replication in tissue culture and produced variants which (i) demonstrated different levels of replication and production of the individual structural proteins, (ii) efficiently induced the antiviral response in infected cells, (iii) were incapable of replication in cells of mosquito origin, and (iv) efficiently replicated in Vero cells. This modular approach to genome design is applicable for the construction of other alphaviruses with a programmed, irreversibly attenuated phenotype.The Alphavirus genus in the Togaviridae family contains almost 30 currently known members, which are distributed on all continents (48). Such a wide distribution implies evolution of the viruses in different, geographically isolated areas and their adaptation to different host and vector species. In mosquito vectors, alphaviruses cause a persistent, life-long infection that does not significantly interfere with the vectors' biological functions (59, 60). These viruses accumulate to high concentrations in mosquito salivary glands and are transmitted to vertebrate hosts during the blood meal. In vertebrates, alphaviruses develop an acute infection, characterized by a high-titer viremia, required for virus transmission to new mosquitoes during blood ingestion and continuation of the infection cycle. The high rates of alphavirus replication and viremia development are critically determined by efficient function of viral genome replication machinery and rapid accumulation of virus-specific structural proteins in the infected cells. However, another important contributor to the infectious process is the abilit...

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Alphavirus replicon particles acting as adjuvants promote CD8+ T cell responses to co-delivered antigen

Cited by 35 publications

References 52 publications

Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus

Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus

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

Design of Chimeric Alphaviruses with a Programmed, Attenuated, Cell Type-Restricted Phenotype

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