Mechanisms of Immunization with a Replication-Defective Mutant of Herpes Simplex Virus 1

Morrison, Lynda A.; Knipe, David M.

doi:10.1006/viro.1996.0328

Cited by 67 publications

(89 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Female BALB/c mice were obtained from Taconic Farms (Germantown, N.Y.) and housed in accordance with institutional and National Institutes of Health guidelines on the care and use of animals in research. Immunization of mice was performed as described previously (26). Six-week-old female BALB/c mice were randomized into four groups of six mice each.…”

mentioning

confidence: 99%

Construction, Phenotypic Analysis, and Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex Virus 2

Costa

Kramer

Zhu

et al. 2000

J Virol

Self Cite

View full text Add to dashboard Cite

A number of studies have shown that replication-defective mutant strains of herpes simplex virus (HSV) can induce protective immunity in animal systems against wild-type HSV challenge. However, all of those studies used viruses with single mutations. Because multiple, stable mutations provide optimal levels of safety for live vaccines, we felt that additional mutations needed to be engineered into a candidate vaccine strain for HSV-2 and genital herpes. We therefore isolated an HSV-2 strain with deletion mutations in two viral DNA replication protein genes, UL5 and UL29. The resulting double deletion mutant virus strain, dl5-29, fails to form plaques or to give any detectable single cycle yields in normal monkey or human cells. Nevertheless, dl5-29 expresses nearly the same pattern of gene products as the wild-type virus or the single mutant viruses and induces antibody titers in mice that are equivalent to those induced by single deletion mutant viruses. Therefore, it is feasible to isolate a mutant HSV strain with two mutations in essential genes and with an increased level of safety but which is still highly immunogenic.

show abstract

mentioning

confidence: 99%

Construction, Phenotypic Analysis, and Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex Virus 2

Costa

Kramer

Zhu

et al. 2000

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Immunization of mice with either wild-type virus or replication-defective HSV-1 recombinants leads to reduction of challenge virus in the establishment of latent infection (38,39). On the basis that immunization with CJ83193 can significantly reduce the replication of challenge virus in the eyes and trigeminal ganglia of mice, we tested whether the efficiency of latent infection by challenge virus in trigeminal ganglia of mice could also be reduced by immunization with CJ83193.…”

Section: Vol 78 2004mentioning

confidence: 99%

The Dominant-Negative Herpes Simplex Virus Type 1 (HSV-1) Recombinant CJ83193 Can Serve as an Effective Vaccine against Wild-Type HSV-1 Infection in Mice

Augustinova

Hoeller

Yao

2004

J Virol

View full text Add to dashboard Cite

By selectively regulating the expression of the trans-dominant-negative mutant polypeptide UL9-C535C, of herpes simplex virus type 1 (HSV-1) origin binding protein UL9 with the tetracycline repressor (tetR)-mediated gene switch, we recently generated a novel replication-defective and anti-HSV-specific HSV-1 recombinant, CJ83193. The UL9-C535C peptides expressed by CJ83193 can function as a potent intracellular therapy against its own replication, as well as the replication of wild-type HSV-1 and HSV-2 in coinfected cells. In this report, we demonstrate that CJ83193 cannot initiate acute productive infection in corneas of infected mice nor can it reactivate from trigeminal ganglia of mice latently infected by CJ83193 in a mouse ocular model. Given that CJ83193 is capable of expressing the viral ␣, ␤, and ␥1 genes but little or no ␥2 genes, we tested the vaccine potential of CJ83193 against HSV-1 infection in a mouse ocular model. Our studies showed that immunization with CJ83193 significantly reduced the yields of challenge HSV in the eyes and trigeminal ganglia on days 3, 5, and 7 postchallenge. Like in mice immunized with the wild-type HSV-1 strain KOS, immunization of mice with CJ83193 prevents the development of keratitis and encephalitis induced by corneal challenge with wild-type HSV-1 strain mP. Delayed-type hypersensitivity (DTH) assays demonstrate that CJ83193 can elicit durable cell-mediated immunity at the same level as that of wild-type HSV-1 and is more effective than that induced by d27, an HSV-1 ICP27 deletion mutant. Moreover, mice immunized with CJ83193 developed strong, durable HSV-1-neutralizing antibodies at levels at least twofold higher than those induced by d27. The results presented in this report have shed new light on the development of effective HSV viral vaccines that encode a unique safety mechanism capable of inhibiting the mutant's own replication and that of wild-type virus.Herpesviruses can cause both an acute productive infection and a long-term latent infection characterized by periodic recurrences (54). Among the human herpesviruses, herpes simplex virus types 1 and type 2 (HSV-1 and -2, respectively) are most closely related and share significant DNA sequence homology (15,31,32). Although HSV infections are often asymptomatic, their clinical manifestations include oral-facial infections, genital herpes, neonatal herpes, keratoconjunctivitis, and herpes encephalitis (48,54). Despite the availability of various effective antiviral therapies, the spread of genital herpes infection continues to increase worldwide and has increased by 30% in the United States in the past two decades (19). The failure of antiviral therapy in effectively controlling the spread of HSV disease and the life-long nature of the infection present a strong need for developing safe and efficacious vaccines against HSV infections (48, 54).HSV replicates in epithelial cells and establishes life-long latent infection in neuronal cell bodies within the sensory ganglia of infected individuals. During productive i...

show abstract

“…Both rodent and nonhuman primate models for comparing the relative virulence of HSV-1 and HSV2 strains have been described (27)(28)(29)(43)(44)(45)(46)(47). None of these models, including Aotus monkey models, fully recapitulate HSV-1 infection observed in humans.…”

Section: Figurementioning

confidence: 99%

“…Aotus monkeys are both expensive and difficult to acquire for research purposes. The mouse model has several advantages compared with the Aotus monkey model, including the absence of any ambiguity over the strain or age of the animals (44,45), ability to examine toxicity in several animals for each dose level and each strain of HSV-1, significantly greater research experience with this model, and the absence of significant logistical or financial barriers. We demonstrated that the LD 50 of Myb34.5 is at least one log order greater than that of hrR3 and at least two log orders greater than that of wild-type F strain in a mouse model.…”

Section: Figurementioning

confidence: 99%

“…For example, HSV-1 mutants R3616 and MGH1 are both completely defective in their expression of γ 1 34.5, and the magnitude of their replication is significantly attenuated compared with that of wildtype HSV-1 (15,20). MGH1 is essentially identical to another HSV-1 mutant, G207 (45,56,57), which has been examined in a clinical trial for brain tumor patients (58) and is presently under examination for treatment of liver tumors. These HSV-1 mutants are defective in both γ 1 34.5 and viral ribonucleotide reductase expression.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Regulation of herpes simplex virus γ134.5 expression and oncolysis of diffuse liver metastases by Myb34.5

Nakamura¹,

Kasuya²,

Mullen³

et al. 2002

J. Clin. Invest.

View full text Add to dashboard Cite

Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of γ 1 34.5 (a viral gene product that promotes the dephosphorylation of eIF-2α) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). γ 1 34.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2α dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in γ 1 34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2α dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in γ 1 34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective γ 1 34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type γ 1 34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type γ 1 34.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab's to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo. reductase), is effectively complemented by liver metastases but not by normal liver, which results in hrR3 replication preferentially in liver metastases rather than in normal liver. However, hrR3 can replicate at low levels in non-neoplastic cells and demonstrates virulence in vivo at high titer. Accordingly, we have concentrated our efforts on development and characterization of an HSV-1 mutant that is as effective in its oncolytic potential, but less toxic and virulent in vivo.Myb34.5 is a second-generation replication-conditional HSV-1 mutant in which ICP6 expression is defective and expression of the HSV-1 γ 1 34.5 gene is regulated by the cellular B-myb promoter (14). Following HSV-1 infection, γ 1 34.5 normally interacts with the cellular protein phosphatase-1α, which leads to eIF-2α dephosphorylation (Figure 1) (15)(16)(17)(18). This allows initiation of protein translation to proceed, which is necessary for robust viral replication. HSV-1 mutants with completely defective γ 1 34.5 expression display significantly attenuated replication in both normal and neoplastic cells. In contrast, regulation of γ 1 34.5 expression by the cellular B-myb promoter following infection by Myb34.5 theoretically permits γ 1 34.5 expression in cycling cells and in cells with deregulated E2F activation. Accordingly, Myb34.5 replication in quiescent cells should be more attenuated than that of ICP6-defective HSV-1 mutants with normal γ 1 3...

show abstract

Mechanisms of Immunization with a Replication-Defective Mutant of Herpes Simplex Virus 1

Cited by 67 publications

References 8 publications

Construction, Phenotypic Analysis, and Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex Virus 2

Construction, Phenotypic Analysis, and Immunogenicity of a UL5/UL29 Double Deletion Mutant of Herpes Simplex Virus 2

The Dominant-Negative Herpes Simplex Virus Type 1 (HSV-1) Recombinant CJ83193 Can Serve as an Effective Vaccine against Wild-Type HSV-1 Infection in Mice

Regulation of herpes simplex virus γ134.5 expression and oncolysis of diffuse liver metastases by Myb34.5

Contact Info

Product

Resources

About