Restricted and Selective Tropism of a Venezuelan Equine Encephalitis Virus-Derived Replicon Vector for Human Dendritic Cells

Nishimoto, Kevin; Laust, Amanda K.; Wang, Kehui; Kamrud, Kurt I.; Hubby, Bolyn; Smith, Jonathan; Nelson, Edward L.

doi:10.1089/vim.2006.0090

Cited by 34 publications

(36 citation statements)

References 80 publications

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“…Given that dendritic cells are phenotypically heterogeneous, the exact type of dendritic cells infected in vivo remains to be determined. That alphaviruses can infect dendritic cells has been reported for RRV, Sindbis, and Venezuelan equine encephalitis viruses (61)(62)(63).…”

Section: Figurementioning

confidence: 82%

Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

Labadie¹,

Larcher²,

Joubert³

et al. 2010

J. Clin. Invest.

475

604

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Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, muscles, lymphoid organs, and liver, which could explain the long-lasting CHIKV disease symptoms observed in humans. In addition, the study identified macrophages as the main cellular reservoirs during the late stages of CHIKV infection in vivo. This model of CHIKV physiopathology should allow the development of new therapeutic and/or prophylactic strategies.

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Section: Figurementioning

confidence: 82%

Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

Labadie¹,

Larcher²,

Joubert³

et al. 2010

J. Clin. Invest.

475

604

View full text Add to dashboard Cite

show abstract

“…The VRP, VSV, and adenovirus-based vaccines are the only filovirus vaccine candidates to provide full protection to NHPs after only one vaccination (19,41,42). 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).…”

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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“…Alternatively, GVI3000 particles can migrate directly to DLNs, where they preferentially target DCs (36,37). In both human-and mouse-derived DCs, in vitro studies have shown an upregulation of costimulatory molecules as well as secretion of proinflammatory cytokines, such as type I IFN, IL-6, and TNF after infection (37)(38)(39). In adult mice, cytokine secretion was observed systemically and in the DLNs as soon as 6 h after GVI3000 inoculation (unpublished observation).…”

mentioning

confidence: 93%

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

Khalil

Tonkin

Snead

et al. 2014

J Virol

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Neonatal immune responses to infection and vaccination are biased toward T H 2 at the cost of proinflammatory T H 1 responses needed to combat intracellular pathogens. However, upon appropriate stimulation, the neonatal immune system can induce adult-like T H 1 responses. Here we report that a new class of vaccine adjuvant is especially well suited to enhance early life immunity. The GVI3000 adjuvant is a safe, nonpropagating, truncated derivative of Venezuelan equine encephalitis virus that targets dendritic cells (DCs) in the draining lymph node (DLN) and produces intracellular viral RNA without propagating to other cells. RNA synthesis strongly activates the innate immune response so that in adult animals, codelivery of soluble protein antigens induces robust humoral, cellular, and mucosal responses. The adjuvant properties of GVI3000 were tested in a neonatal BALB/c mouse model using inactivated influenza virus (iFlu). After a single immunization, mice immunized with iFlu with the GVI3000 adjuvant (GVI3000-adjuvanted iFlu) had significantly higher and sustained influenza virus-specific IgG antibodies, mainly IgG2a (T H 1), compared to the mice immunized with antigen only. GVI3000 significantly increased antigen-specific CD4؉ and CD8 ؉ T cells, primed mucosal immune responses, and enhanced protection from lethal challenge. As seen in adult mice, the GVI3000 adjuvant increased the DC population in the DLNs, caused activation and maturation of DCs, and induced proinflammatory cytokines and chemokines in the DLNs soon after immunization, including gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). In summary, the GVI3000 adjuvant induced an adult-like adjuvant effect with an influenza vaccine and has the potential to improve the immunogenicity and protective efficacy of new and existing neonatal vaccines. IMPORTANCEThe suboptimal immune responses in early life constitute a significant challenge for vaccine design. Here we report that a new class of adjuvant is safe and effective for early life immunization and demonstrate its ability to significantly improve the protective efficacy of an inactivated influenza virus vaccine in a neonatal mouse model. The GVI3000 adjuvant delivers a truncated, self-replicating viral RNA into dendritic cells in the draining lymph node. Intracellular RNA replication activates a strong innate immune response that significantly enhances adaptive antibody and cellular immune responses to codelivered antigens. A significant increase in protection results from a single immunization. Importantly, this adjuvant also primed a mucosal IgA response, which is likely to be critical for protection during many early life infections.

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Restricted and Selective Tropism of a Venezuelan Equine Encephalitis Virus-Derived Replicon Vector for Human Dendritic Cells

Cited by 34 publications

References 80 publications

Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages

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

An Alphavirus-Based Adjuvant Enhances Serum and Mucosal Antibodies, T Cells, and Protective Immunity to Influenza Virus in Neonatal Mice

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