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Use of the Guinea pig model of genital herpes to evaluate vaccines and antivirals: Review.

ABSTRACT: Herpes simplex virus (HSV) infections type 1 (HSV-1) and type 2 (HSV-2) are common throughout the world. Infections are lifelong and may produce both acute and recurrent vesiculoulcerative disease as well as more severe diseases. Despite disappointing results from recent HSV vaccine trials new vaccines and more potent antiviral therapies continue to be developed. These newer approaches require initial evaluations in animal models. In this review I have briefly described some of the models available and then more thoroughly describe the guinea pig model of acute and recurrent genital herpes infections. As discussed, the guinea pig model most closely mimics human disease and provides several important endpoints for evaluating vaccines and antivirals.

SUBMITTER: Bernstein DI

PROVIDER: S-EPMC10713199 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Use of the Guinea pig model of genital herpes to evaluate vaccines and antivirals: Review.

Bernstein David I DI

Antiviral research 20200613

Herpes simplex virus (HSV) infections type 1 (HSV-1) and type 2 (HSV-2) are common throughout the world. Infections are lifelong and may produce both acute and recurrent vesiculoulcerative disease as well as more severe diseases. Despite disappointing results from recent HSV vaccine trials new vaccines and more potent antiviral therapies continue to be developed. These newer approaches require initial evaluations in animal models. In this review I have briefly described some of the models availa ...[more]

PMID: 32544409

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Project description:Herpes simplex virus (HSV) infections are common and can cause severe illness but no vaccine is currently available. The recent failure of subunit HSV vaccines has highlighted the need for vaccines that present a diverse array of antigens, including the development of next-generation live-attenuated vaccines. However, most attenuated HSV strains propagate poorly, limiting their ability to elicit protective immune responses. A live-attenuated vaccine that replicates in non-neural tissue but is ablated for transmission into the nervous system may elicit protective immune responses without evoking neurologic complications or establishing life-long infections. Initial studies of R2, a live-attenuated vaccine that is engineered to be unable to invade the nervous system, used the guinea pig genital HSV model to evaluate the ability of R2 to replicate at the site of inoculation, cause disease and infect neural tissues. R2 was then evaluated as a vaccine using three routes of inoculation: intramuscular (IM), intradermal (ID) and intravaginal (IVag) and compared to IM administered gD2+MPL/Alum vaccine in the same model. R2 replicated in the genital tract but did not produce acute or recurrent disease and did not infect the neural tissue. The R2 vaccine-induced neutralizing antibody and decreased the severity of acute and recurrent HSV-2 disease as well as recurrent shedding. The ID route was the most effective. ID administered R2 was more effective than gD2+MPL/Alum at inducing neutralizing antibody, suppressing acute disease, and acute vaginal virus replication. R2 was especially more effective at reducing recurrent virus shedding, the most common source of HSV transmission. The live-attenuated prophylactic HSV vaccine, R2, was effective in the guinea pig model of genital HSV-2 especially when administered by the ID route. The use of live-attenuated HSV vaccines that robustly replicate in mucosal tissues but are ablated for neuroinvasion offers a promising approach for HSV vaccines.

Project description:Despite the long-standing observation that herpes simplex virus (HSV) latency-associated transcript (LAT) promoter deletion viruses show impaired recurrence phenotypes in relevant animal models, the mechanism by which these sequences exert this phenotypic effect is unknown. We constructed and evaluated four mutant HSV-2 isolates with targeted mutations in the LAT promoter and LAT-associated microRNAs (miRNAs) affecting (i) the LAT TATA box; (ii) the LAT ICP4-binding site; (iii) miRNA I (miR-I) and miR-II (miR-I/II), which both target ICP34.5; and (iv) miR-III, which targets ICP0. While the LAT TATA box mutant caused milder acute infections than wild-type (WT) virus, there was no difference in the recurrence phenotype between these viruses. LAT and miRNA expression during latency was not impaired by this mutation, suggesting that other promoter elements may be more important for latent HSV-2 LAT expression. Mutation of the LAT ICP4-binding site also did not cause an in vivo phenotypic difference between mutant and WT viruses. Acute infection and reactivation from latency of the miR-I/II mutant were similar to those of its rescuant, although the acute infection was slightly reduced in severity relative to that caused by the wild-type virus. The miR-III mutant also exhibited WT phenotypes in acute and recurrent phases of infection. While they do not rule out an effect of these elements in human latency or reactivation, these findings do not identify a specific role for LAT or LAT-associated miRNAs in the HSV-2 LAT promoter deletion phenotype in guinea pigs. Thus, other sequences in this region may play a more important role in the long-studied LAT-associated phenotype in animals.IMPORTANCE While it has been known for several decades that specific HSV-1 and HSV-2 sequences near the LAT promoter are required for efficient viral reactivation in animal models, the mechanism is still not known. We constructed four mutant viruses with the goal of identifying critical sequence elements and of specifically testing the hypothesis that microRNAs that are expressed during latency play a role. Determination that specific LAT promoter sequences and miRNA sequences do not influence viral reactivation of HSV-2 helps to narrow down the search for the mechanism by which the virus controls its latency and recurrence phenotype.

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Use of the Guinea pig model of genital herpes to evaluate vaccines and antivirals: Review.

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Use of the Guinea pig model of genital herpes to evaluate vaccines and antivirals: Review.

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