Emergence of Herpes Simplex Virus-1 Syncytial Variants With Altered Virulence for Mice After Selection With a Natural Carrageenan

Background: Antiviral therapy against herpes simplex virus based on sulfated polysaccharides, like carrageenans, represents a new alternative for genital herpes infections treatment and arises the concern about the appearance of resistant viral populations. Methods: We characterized the F strain of herpes simplex virus-1 passaged in the presence of a natural carrageenan isolated from the red seaweed Gigartina skottbergii in view of the virulence for mice of isolated viral clones. Results: Viral clones (syn14-1 and syn17-2) showed a syncytial phenotype and a mild resistance to carrageenan, heparin, acyclovir, and brivudine. Both clones were avirulent for BALB/c mice when inoculated intravaginally, whereas F strain produced high mortality. Attenuation correlated with low levels of TNF-&agr;, interleukin-6, and IFN-&ggr; in vaginal lavages although virus titers were similar to those obtained for F strain. On the contrary, they showed a marked virulence when inoculated intranasally leading to a generalized spreading of virus. Conclusions: Results confirm the hypothesis that selection of herpes simplex virus-1 with a carrageenan in vitro leads to the emergence of variants with a differential virulence when compared to the original virus. This finding should be addressed when an antiviral therapy against genital herpes infection employing a natural carrageenan is under consideration.

[1]  J. Burgos,et al.  ICP47 mediates viral neuroinvasiveness by induction of TAP protein following intravenous inoculation of herpes simplex virus type 1 in mice , 2006, Journal of NeuroVirology.

[2]  K. Tyler,et al.  Pathogenesis of Viral Infections , 2010 .

[3]  N. de Vos,et al.  Monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using real-time PCR: a prospective study. , 2009, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[4]  B. Friedland,et al.  Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial , 2008, The Lancet.

[5]  J. Davis,et al.  Effect of IL-6 deficiency on susceptibility to HSV-1 respiratory infection and intrinsic macrophage antiviral resistance. , 2008, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[6]  A. Gettie,et al.  Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity , 2008, PloS one.

[7]  R. Maguire.  Microbicide product development , 2008, Current opinion in HIV and AIDS.

[8]  V. Smit,et al.  Quantitative detection of herpes simplex virus DNA in the lower respiratory tract , 2007, Journal of medical virology.

[9]  H. Agut,et al.  Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. , 2007, American journal of respiratory and critical care medicine.

[10]  D. Phillips,et al.  Carrageenan/MIV-150 (PC-815), a Combination Microbicide , 2007, Sexually transmitted diseases.

[11]  M. Smyth,et al.  NK cells contribute to the early clearance of HSV‐1 from the lung but cannot control replication in the central nervous system following intranasal infection , 2006, European journal of immunology.

[12]  E. De Clercq,et al.  Characterization of Herpes Simplex Virus Type 1 Thymidine Kinase Mutants Selected under a Single Round of High-Dose Brivudin , 2005, Journal of Virology.

[13]  B. Lina,et al.  Herpes Simplex Virus Thymidine Kinase Mutations Associated with Resistance to Acyclovir: a Site-Directed Mutagenesis Study , 2005, Antimicrobial Agents and Chemotherapy.

[14]  F. B. Johnson,et al.  Identification of syncytial mutations in a clinical isolate of herpes simplex virus 2. , 2004, Virology.

[15]  T. Quinn,et al.  The Effects of Herpes Simplex Virus-2 on HIV-1 Acquisition and Transmission: A Review of Two Overlapping Epidemics , 2004, Journal of acquired immune deficiency syndromes.

[16]  J. Sasadeusz,et al.  Molecular analysis of clinical isolates of acyclovir resistant herpes simplex virus. , 2004, Antiviral research.

[17]  Wiley Interscience,et al.  Herpes simplex type 1 shedding is associated with reduced hospital survival in patients receiving assisted ventilation in a tertiary referral intensive care unit , 2004, Journal of medical virology.

[18]  L. Stanberry,et al.  Is herpes simplex virus type 1 (HSV-1) now more common than HSV-2 in first episodes of genital herpes? , 2003, Sexually transmitted diseases.

[19]  M. Arsenakis,et al.  A single amino acid substitution in the cytoplasmic tail of the glycoprotein B of herpes simplex virus 1 affects both syncytium formation and binding to intracellular heparan sulfate. , 2003, Virus research.

[20]  D. Thouvenot,et al.  Herpes simplex virus resistance to antiviral drugs. , 2003, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[21]  E. Damonte,et al.  Herpes simplex virus type 1 variants arising after selection with an antiviral carrageenan: Lack of correlation between drug susceptibility and syn phenotype , 2002, Journal of medical virology.

[22]  Jian Liu,et al.  Cell surface heparan sulfate and its roles in assisting viral infections , 2002, Medicinal research reviews.

[23]  B. Svennerholm,et al.  Herpes Simplex Virus Types 1 and 2 Differ in Their Interaction with Heparan Sulfate , 2000, Journal of Virology.

[24]  M. Levin,et al.  Increased excretion of urinary glycosaminoglycans in meningococcal septicemia and their relationship to proteinuria , 2000, Critical care medicine.

[25]  A. Wald,et al.  Herpes simplex virus: the importance of asymptomatic shedding. , 2000, The Journal of antimicrobial chemotherapy.

[26]  E. Damonte,et al.  Inhibitory Action of Natural Carrageenans on Herpes simplex Virus Infection of Mouse Astrocytes , 1999, Chemotherapy.

[27]  E. Damonte,et al.  Antiherpetic activity and mode of action of natural carrageenans of diverse structural types. , 1999, Antiviral research.

[28]  J. Platt,et al.  Regulation of platelet heparanase during inflammation: Role of pH and proteinases , 1998, Journal of cellular physiology.

[29]  Hao Wang,et al.  Syndecans, Heparan Sulfate Proteoglycans, Maintain the Proteolytic Balance of Acute Wound Fluids* , 1998, The Journal of Biological Chemistry.

[30]  G. Darby,et al.  Survey of Resistance of Herpes Simplex Virus to Acyclovir in Northwest England , 1998, Antimicrobial Agents and Chemotherapy.

[31]  L. Corey,et al.  Perspectives on switching oral acyclovir from prescription to over-the-counter status: report of a consensus panel. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  E. Damonte,et al.  Antiherpetic and anticoagulant properties of carrageenans from the red seaweed Gigartina skottsbergii and their cyclized derivatives: correlation between structure and biological activity. , 1997, International journal of biological macromolecules.

[33]  P. Spear,et al.  Modified entry and syncytium formation by herpes simplex virus type 1 mutants selected for resistance to heparin inhibition. , 1996, Virology.

[34]  D. Falke,et al.  Single amino acid substitutions in the glycoprotein B carboxy terminus influence the fusion from without property of herpes simplex virus type 1. , 1995, The Journal of general virology.

[35]  N. Davis-Poynter,et al.  Mutations in the cytoplasmic tail of herpes simplex virus glycoprotein H suppress cell fusion by a syncytial strain , 1994, Journal of virology.

[36]  J. Verhoef,et al.  Binding of surfactant protein A (SP-A) to herpes simplex virus type 1-infected cells is mediated by the carbohydrate moiety of SP-A. , 1992, The Journal of biological chemistry.

[37]  J. L. Goodman,et al.  Altered pathogenesis in herpes simplex virus type 1 infection due to a syncytial mutation mapping to the carboxy terminus of glycoprotein B , 1991, Journal of virology.

[38]  B. Herold,et al.  Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity , 1991, Journal of virology.

[39]  P. Spear,et al.  Initial interaction of herpes simplex virus with cells is binding to heparan sulfate , 1989, Journal of virology.

[40]  M. Sarmiento.  Intrinsic resistance to viral infection. Mouse macrophage restriction of herpes simplex virus replication. , 1988, Journal of immunology.

[41]  J. Sodroski,et al.  Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus , 1987, Nature.

[42]  P. Lazo.  Pathogenesis of viral infections. , 1985, The New England journal of medicine.

[43]  J. A. Bradley,et al.  Herpes simplex virus reactivation in surgical patients , 1984, Critical care medicine.

[44]  P. Spear,et al.  Alterations in Glycoprotein gB Specified by Mutants and Their Partial Revertants in Herpes Simplex Virus Type 1 and Relationship to Other Mutant Phenotypes , 1980, Journal of virology.