Recombinant rabies virus as potential live-viral vaccines for HIV-1

Schnell, Matthias J.; Foley, H.; Siler, Catherine A.; McGettigan, James P.; Dietzschold, Bernhard; Pomerantz, Roger J.

doi:10.1073/pnas.97.7.3544

Cited by 88 publications

(76 citation statements)

References 38 publications

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“…Preclinical as well as clinical trials with these constructs yielded disappointing results as the neutralizing Abs induced by such vaccines lacked the breath to provide solid protection against different HIV-1 isolates (21,22). Subsequent vaccine efforts were directed at inducing cell-mediated immune responses (6,(23)(24)(25). Optimized DNA vaccines expressing the gag of HIV-1 provided initial protection to nonhuman primates challenged with SHIV-89.6P virus (26).…”

Section: Discussionmentioning

confidence: 99%

Induction of CD8+ T Cells to an HIV-1 Antigen through a Prime Boost Regimen with Heterologous E1-Deleted Adenoviral Vaccine Carriers

Pinto

Fitzgerald

Giles-Davis

et al. 2003

The Journal of Immunology

106

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E1-deleted adenoviral recombinants most commonly based on the human serotype 5 (AdHu5) have been shown thus far to induce unsurpassed transgene product-specific CD8+ T cell responses. A large percentage of the adult human population carries neutralizing Abs due to natural exposures to AdHu5 virus. To circumvent reduction of the efficacy of adenovirus (Ad) vector-based vaccines by neutralizing Abs to the vaccine carrier, we developed E1-deleted adenoviral vaccine carriers based on simian serotypes. One of these carriers, termed AdC68, expressing a codon-optimized truncated form of gag of HIV-1 was shown previously to induce a potent transgene product-specific CD8+ T cell response in mice. We constructed a second chimpanzee adenovirus vaccine vector, termed AdC6, also expressing the truncated gag of HIV-1. This vector, which belongs to a different serotype than the AdC68 virus, induces high frequencies of gag-specific CD8+ T cells in mice including those pre-exposed to AdHu5 virus. Generation of an additional E1-deleted adenoviral vector of chimpanzee origin allows for sequential booster immunizations with heterologous vaccine carriers. In this study, we show that such heterologous prime boost regimens based on E1-deleted adenoviral vectors of different serotypes expressing the same transgene product are highly efficient in increasing the transgene product-specific CD8+ T cell response. They are equivalent to sequential vaccinations with an E1-deleted Ad vector followed by booster immunization with a poxvirus vector and they surpass regimens based on DNA vaccine prime followed by a recombinant adenoviral vector boost.

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Section: Discussionmentioning

confidence: 99%

Induction of CD8+ T Cells to an HIV-1 Antigen through a Prime Boost Regimen with Heterologous E1-Deleted Adenoviral Vaccine Carriers

Pinto

Fitzgerald

Giles-Davis

et al. 2003

The Journal of Immunology

106

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“…For experiments involving recovery of the recombinant RVs, the previously described RV recovery system was used (9,28). Briefly, BSR T7 cells (3), which stably express T7 RNA polymerase, were transfected with 5 g of full-length RV cDNA (SPBN-333-Gag, SPBN-⌬CD-Gag, SPBN-333-⌬CD-Gag, BNSP-Gag, and BNSP) in addition to plasmids encoding the RV N, P, L, and G proteins by using a Ca 2 PO 4 transfection kit (Stratagene), as instructed by the vendor.…”

Section: Methodsmentioning

confidence: 99%

Second-Generation Rabies Virus-Based Vaccine Vectors Expressing Human Immunodeficiency Virus Type 1 Gag Have Greatly Reduced Pathogenicity but Are Highly Immunogenic

McGettigan

Pomerantz²,

Siler³

et al. 2003

J Virol

Self Cite

130

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Rabies virus (RV) vaccine strain-based vectors show great promise as vaccines against other viral diseases such as human immunodeficiency virus type 1 (HIV-1) infection and hepatitis C, but a low residual pathogenicity remains a concern for their use. Here we describe several highly attenuated second-generation RV-based vaccine vehicles expressing HIV-1 Gag. For this approach, we modified the previously described RV vaccine vector SPBN by replacing the arginine at position 333 (R333) within the RV glycoprotein (G) with glutamic acid (E333), deleting 43 amino acids of the RV G cytoplasmic domain (CD), or combining the R333 exchange and the CD deletion. In addition, we constructed a new RV vector that expresses HIV-1 Gag from an RV transcription unit upstream of the RV phosphoprotein gene (BNSP-Gag) instead of upstream of the G gene. As expected and as demonstrated for SPBN-Gag, all vaccine vehicles were apathogenic after peripheral administration. However, the new, second-generation vaccine vectors containing modifications in the RV G were also apathogenic after intracranial infection with 10 5 infectious particles, and BNSP-Gag produced a 50%-reduced mortality in mice. Of note, the observed attenuation of pathogenicity did not result in either the attenuation of the humoral response against the RV G or the previously observed robust cellular response against HIV-1 Gag. These findings demonstrate that very safe and highly effective RV-based vaccines can be constructed and further emphasize their potential utility as efficacious antiviral vaccines.Rabies virus (RV) is a nonsegmented negative-strand RNA virus of the Rhabdoviridae family. The 12-kb RV genome encodes five monocistronic RNAs encoding the nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), the single transmembrane protein G, and the viral polymerase (L). The RV virion consists of an internal core or ribonucleoprotein (RNP) complex, which is composed of the viral RNA encased in the N protein and associated with P and L (32) and an external component, the viral envelope, which consists of the host-cell derived membrane with the M protein located at its inner surface and the membrane-spanning G protein (18,19). The G protein is responsible for both the interaction with a cellular receptor(s) and pH-dependent membrane fusion (33).RV pathogenicity has been studied for more than 100 years, with research results indicating that RV consists of a wide array of variants. These can range from highly pathogenic strains, such as silver-haired bat virus, to extremely attenuated RV vaccine strains, such as SAG-2, which are not pathogenic in severe combined immunodeficiency (SCID) mice after oral application (20, 23; C. Hanlon, M. Fiorello, C. L. Schumacher, V. Shankar, A. Hamir, and C. Rupprecht, Abstr. 4th Annu. Int. Meet. Adv. Rabies Control Americas, 1993). Two proteins have been associated with RV pathogenesis, namely, P and G. It has been suggested that a specific interaction of a conserved domain within RV P and the cytoplasmic dynein light chain ...

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“…Several groups have attempted to develop vaccine vehicles using RV-based vectors. It has been reported that the RV vectors expressing foreign antigens induce strong humoral and cellular responses against other kinds of viral pathogens, such as human immunodeficiency virus type 1 and hepatitis C virus, in the mouse model (54,55,79,81). The high efficacy of RV in inducing an antiviral immune response may also be due to the stimulation of immunocytes by RV components.…”

mentioning

confidence: 99%

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

Nakamichi¹,

Inoue

Takasaki³

et al. 2004

J Virol

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Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.Rabies virus (RV) is a negative-strand RNA virus belonging to the Rhabdoviridae family, genus Lyssavirus. Most RV strains are highly neurotropic, which usually causes a fatal infection in warm-blooded animals, and viral replication primarily occurs in neurons as a cellular target (43). It has been reported that RV replicates in muscle cells prior to the invasion of the peripheral nervous system and central nervous system (CNS) in vivo (62). In vitro, it is known that a highly neurovirulent RV strain, challenge virus standard (CVS), and an attenuated strain, high egg passage (HEP)-Flury (hereafter called HEP), infect a variety of cell types, including nonneuronal cells (26,82,84,85).It is well known that infection of experimental animals with nonpathogenic RV strains triggers a strong antiviral immune response (90). Recent studies have demonstrated that the strong antiviral immune response elicited by attenuated RV infection is closely related to the induction of apoptosis in infected cells due to the expression of viral glycoprotein (61,76). Several groups have attempted to develop vaccine vehicles using RV-based vectors. It has been reported that the RV vectors expressing foreign antigens induce strong humoral and cellular responses against other kinds of viral pathogens, s...

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Recombinant rabies virus as potential live-viral vaccines for HIV-1

Cited by 88 publications

References 38 publications

Induction of CD8+ T Cells to an HIV-1 Antigen through a Prime Boost Regimen with Heterologous E1-Deleted Adenoviral Vaccine Carriers

Induction of CD8+ T Cells to an HIV-1 Antigen through a Prime Boost Regimen with Heterologous E1-Deleted Adenoviral Vaccine Carriers

Second-Generation Rabies Virus-Based Vaccine Vectors Expressing Human Immunodeficiency Virus Type 1 Gag Have Greatly Reduced Pathogenicity but Are Highly Immunogenic

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

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