Synergy evaluation of anti-Herpes Simplex Virus type 1 and 2 compounds acting on different steps of virus life cycle

Criscuolo, Elena; Clementi, Nicola; Mancini, Nicasio; Burioni, Roberto; Miduri, Marco; Castelli, Matteo; Clementi, Massimo

doi:10.1016/j.antiviral.2018.01.009

Cited by 9 publications

(14 citation statements)

References 26 publications

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“…The observations on serum behavior suggest epitope-tailored vaccine approaches (33) properly eliciting PEI antibodies as well as for the setting up of novel immunotherapeutic regimens targeting HSV types that do not respond to currently available systemic drugs. Regarding the latter, we previously described a neutralizing human IgG that confers full protection from death in animals infected with HSV and that also inhibits the HSV cell-to-cell transmission mechanism (18,19). This provides proof that even naturally elicited anti-gD antibodies are able to block this mechanism, but for some reason they are not particularly common and/or, when present, are probably underrepresented within the blood serum.…”

Section: Discussionmentioning

confidence: 97%

“…PEI assay. The postentry assay was adapted from previous studies (20,38) as previously described (18,19). Confluent monolayers of Vero E6 cells were infected with 100 PFU of virus.…”

Section: Methodsmentioning

confidence: 99%

“…Among the neutralizing monoclonal antibodies (MAbs) described so far, few are of human origin, and only one, IgG#33, previously characterized for its in vivo anti-HSV activity, is endowed with the capability of inhibiting in vitro virus infection of both HSV-1 and -2 after proper virus entry into target cells (18,19). The focus of our attention is not on the fine dissection of antibody subpopulations from a quantitative point of view; instead, we give priority to the study of the biological effect of antibodies present within the sera.…”

mentioning

confidence: 99%

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Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

Criscuolo

Castelli

Diotti

et al. 2019

J Virol

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Herpes simplex virus 1 (HSV-1) and HSV-2 can evade serum antibodymediated neutralization through cell-to-cell transmission mechanisms, which represent one of the central steps in disease reactivation. To address the role of humoral immunity in controlling HSV-1 and HSV-2 replication, we analyzed serum samples from 44 HSV-1 and HSV-2 seropositive subjects by evaluating (i) their efficiency in binding both the purified viral particles and recombinant gD and gB viral glycoproteins, (ii) their neutralizing activity, and (iii) their capacity to inhibit the cell-to-cell virus passage in vitro. All of the sera were capable of binding gD, gB, and whole virions, and all sera significantly neutralized cell-free virus. However, neither whole sera nor purified serum IgG fraction was able to inhibit significantly cell-to-cell virus spreading in in vitro post-virus-entry infectious assays. Conversely, when spiked with an already described anti-gD human monoclonal neutralizing antibody capable of inhibiting HSV-1 and -2 cell-to-cell transmission, each serum boosted both its neutralizing and post-virus-entry inhibitory activity, with no interference exerted by serum antibody subpopulations. IMPORTANCE Despite its importance in the physiopathology of HSV-1 and -2 infections, the cell-to-cell spreading mechanism is still poorly understood. The data shown here suggest that infection-elicited neutralizing antibodies capable of inhibiting cell-to-cell virus spread can be underrepresented in most infected subjects. These observations can be of great help in better understanding the role of humoral immunity in controlling virus reactivation and in the perspective of developing novel therapeutic strategies, studying novel correlates of protection, and designing effective vaccines.

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Section: Discussionmentioning

confidence: 97%

“…PEI assay. The postentry assay was adapted from previous studies (20,38) as previously described (18,19). Confluent monolayers of Vero E6 cells were infected with 100 PFU of virus.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

Criscuolo

Castelli

Diotti

et al. 2019

J Virol

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“…Besides these receptors, additional gD ligands have been identified, such as 3-O-sulfated heparan sulfates which have been proposed to play relevant roles in HSV infections (Shukla et al, 1999 ). In this regard, viral entry can be blocked with antibodies that prevent the interaction between gD and its receptors (Criscuolo et al, 2018 ). For instance, M27f is a monoclonal antibody against gD that has shown neutralizing activity, not only against HSV-1 but also against HSV-2 and that inhibition of the entry process can occur even after attachment of virions to the cell surface (Du et al, 2017 ).…”

Section: Herpes Simplex Virus Entry Into the Host Cellmentioning

confidence: 99%

Experimental Dissection of the Lytic Replication Cycles of Herpes Simplex Viruses in vitro

et al. 2018

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Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) produce lifelong infections and are highly prevalent in the human population. Both viruses elicit numerous clinical manifestations and produce mild-to-severe diseases that affect the skin, eyes, and brain, among others. Despite the existence of numerous antivirals against HSV, such as acyclovir and acyclovir-related analogs, virus variants that are resistant to these compounds can be isolated from immunosuppressed individuals. For such isolates, second-line drugs can be used, yet they frequently produce adverse side effects. Furthermore, topical antivirals for treating cutaneous HSV infections usually display poor to moderate efficacy. Hence, better or novel anti-HSV antivirals are needed and details on their mechanisms of action would be insightful for improving their efficacy and identifying specific molecular targets. Here, we review and dissect the lytic replication cycles of herpes simplex viruses, discussing key steps involved in cell infection and the processes that yield new virions. Additionally, we review and discuss rapid, easy-to-perform and simple experimental approaches for studying key steps involved in HSV replication to facilitate the identification of the mechanisms of action of anti-HSV compounds.

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“…Drug resistance is also virus-mediated and is associated to some extent with the acceleration of natural mutations in the α-herpesvirus TK gene. As these trends continue, the development of safer and more efficient new broad-spectrum antiherpesvirus medications that target different stages of viral replication or different types of infected cells will be advanced (Criscuolo et al., 2018).…”

Section: Conclusion and Directionmentioning

confidence: 99%

Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets

Xie

Wang

et al. 2019

Front. Microbiol.

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Alpha-herpesvirus thymidine kinase (TK) genes are virulence-related genes and are nonessential for viral replication; they are often preferred target genes for the construction of gene-deleted attenuated vaccines and genetically engineered vectors for inserting and expressing foreign genes. The enzymes encoded by TK genes are key kinases in the nucleoside salvage pathway and have significant substrate diversity, especially the herpes simplex virus 1 (HSV-1) TK enzyme, which phosphorylates four nucleosides and various nucleoside analogues. Hence, the HSV-1 TK gene is exploited for the treatment of viral infections, as a suicide gene in antitumor therapy, and even for the regulation of stem cell transplantation and treatment of parasitic infection. This review introduces the effects of α-herpesvirus TK genes on viral virulence and infection in the host and classifies and summarizes the current main application domains and potential uses of these genes. In particular, mechanisms of action, clinical limitations, and antiviral and antitumor therapy development strategies are discussed.

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Synergy evaluation of anti-Herpes Simplex Virus type 1 and 2 compounds acting on different steps of virus life cycle

Cited by 9 publications

References 26 publications

Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

Experimental Dissection of the Lytic Replication Cycles of Herpes Simplex Viruses in vitro

Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets

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