Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogeneic hematopoietic stem cell transplantation

Over an eight-month period from October 1997 to May 1998, four patients who had received bone marrow transplant (BMT) from unrelated donor presented with severe mucosal cutaneous infections involving acyclovir resistant herpes simplex virus 1 (HSV-1). The four isolates were acyclovir (ACV) resistant, three of which were also foscarnet resistant as determined by the dye uptake method. The sequencing of the thymidine kinase (TK) gene did not permit to establish a relation between mutations and resistance to ACV. Three patients were considered as clinically cured of their HSV infection by replacement of ACV or foscarnet with either valacyclovir (one case) or cidofovir (two cases) but eventually two of them died of graft vs host disease. One patient died of extensive HSV infection despite administration of cidofovir. This study emphasizes the importance of monitoring the herpes virus resistance to antiviral drugs in bone marrow transplant recipients and the usefulness of the evaluation of novel antiviral drug for treatment of infections due to strains of HSV resistant to ACV and foscarnet that occur in about 5% of immunocompromised patients.     

Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus

Incomplete coverage and short duration of action limit the effectiveness of vaginally administered drugs, including microbicides, for preventing sexually transmitted infections. We investigated vaginal distribution, retention, and safety of nanoparticles with surfaces modified to enhance transport through mucus. We show that mucus-penetrating particles (MPPs) provide uniform distribution over the vaginal epithelium, whereas conventional nanoparticles (CPs) that are mucoadhesive are aggregated by mouse vaginal mucus, leading to poor distribution. Moreover, when delivered hypotonically, MPPs were transported advectively (versus diffusively) through mucus deep into vaginal folds (rugae) within minutes. By penetrating into the deepest mucus layers, more MPPs were retained in the vaginal tract after 6 hours compared to CPs. After 24 hours, when delivered in a conventional vaginal gel, patches of a model drug remained on the vaginal epithelium, whereas the epithelium was coated with drug delivered by MPPs. We then developed MPPs composed of acyclovir monophosphate (ACVp). When administered before vaginal herpes simplex virus 2 challenge, ACVp-MPPs protected 53% of mice compared to only 16% protected by soluble drug. Overall, MPPs improved vaginal drug distribution and retention, provided more effective protection against vaginal viral challenge than soluble drug, and were nontoxic when administered daily for 1 week.     

Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections

A small number of antiviral drugs are available for the treatment of varicella zoster virus (VZV) and herpes simplex virus (HSV) infections in children. This review presents pharmacokinetic data on the following selected antiviral agents: aciclovir, valaciclovir, famciclovir, cidofovir and foscarnet. Support and current recommendations for the treatment of selected VZV and HSV infections in children will also be reviewed.     

Resistance to vaginal or systemic infection with herpes simplex virus type 2

Summary Mortality due to vaginal or intravenous infection of female BALB/c mice with herpes simplex virus type 2 (HSV-2) was significantly reduced by treatment of mice with the immunomodulator pyran. Following intravaginal inoculation with virus, the incidence of vaginal infection and titers of virus present in the vaginal secretions were significantly reduced in pyran treated as compared with control mice. Vaginal infection did not elicit neutralizing antibody activity in either untreated or pyran treated mice. Intravenous HSV-2 infection did elicit virus specific humoral and delayed type hypersensitivity responses. However, pyran treatment markedly reduced the incidence of these immune responses as compared with those in control intravenously infected mice. Moreover, mice surviving the initial vaginal or intravenous infection with HSV-2 were resistant to subsequent rechallenge by the same route. Pyran treatment did not enhance resistance to vaginal rechallenge, while pyran treated mice were not resistant to intravenous rechallenge. Thus, the antiviral protection mediated by pyran does not appear to involve enhancement of specific humoral or cellular immune responses. Nonspecific host mediated resistance may be involved in the protective effect of the immunomodulator, as suggested by the ability of pyran activated peritoneal cells to inhibit HSV-2 growthin vitro and to transfer resistance to recipient mice challenged with the virus.With 1 Figure     

Combined antiherpetic effect of complex preparation “Viferon® — eye drops” and modified nucleosides

Ready dosage form (eye drops) prepared on the basis of recombinant α₂-IFN exhibits high activity towards herpes simplex type 1 virus in vitro. Systematic study of the antiherpesvirus effect of this drug in combination with modified nucleosides showed an inhibitory effect of the synergic type. Combination of IFN preparation with some nucleosides, including ribavirin, proved to be highly effective towards drug-resistant herpes virus. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 6, pp. 672–675, June, 2006     

A novel chitosan-based thermosensitive hydrogel containing doxorubicin liposomes for topical cancer therapy

Thermosensitive hydrogel containing drug-loaded liposomes delivery system offers the possibility of reduced dosing frequency and sustained drug action. In the study, a soluble chitosan derivative, N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride, was used and interacted with glycerophosphate to produce a thermosensitive hydrogel as the matrix of doxorubicin-loaded liposomes. The formulation could retain the liquid state with good fluidity below or at room temperature for long time but turn into a nonflowing gel after exposing to body temperature for no more than 5?min. The mean size of liposomes was increased when dispersed into the hydrogel, while the entrapment efficiency of doxorubicin in liposomes was not discounted by the hydrogel, which was over 90%. The in vitro release experiment performed with a dialysis membrane model showed that the liposomes-containing hydrogel exhibited an excellent sustained-release behavior, which eliminated the initial burst release occuring in the liposomal formulation and only released about 22% loaded drug in 9?days. In vivo antitumor activity was evaluated by the survival time of H22-bearing mice treated with various doxorubicin formulation, which showed that the hydrogel enhanced the antitumor activity and reduced the systemic toxicity. Thus, all these results demonstrated that the thermosensitive hydrogel with embedded liposomes is a promising antitumor drug carrier for topical cancer therapy.     

Clinical uses of cidofovir

Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross-resistance to cidofovir in ganciclovir-resistant clinical DNA polymerase mutants has been identified. Cross-resistance of cidofovir and foscarnet has not been identified to date. A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications. Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposi's sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic instillation for treatment of viral keratoconjunctivitis. © 1997 John Wiley & Sons, Ltd.     

Iminosugars: Promising therapeutics for influenza infection

Influenza virus causes three to five million severe respiratory infections per year in seasonal epidemics, and sporadic pandemics, three of which occurred in the twentieth century and are a continuing global threat. Currently licensed antivirals exclusively target the viral neuraminidase or M2 ion channel, and emerging drug resistance necessitates the development of novel therapeutics. It is believed that a host-targeted strategy may combat the development of antiviral drug resistance. To this end, a class of molecules known as iminosugars, hydroxylated carbohydrate mimics with the endocyclic oxygen atom replaced by a nitrogen atom, are being investigated for their broad-spectrum antiviral potential. The influenza virus glycoproteins, hemagglutinin and neuraminidase, are susceptible to inhibition of endoplasmic reticulum α-glucosidases by certain iminosugars, leading to reduced virion production or infectivity, demonstrated by in vitro and in vivo studies. In some experiments, viral strain-specific effects are observed. Iminosugars may also inhibit other host and virus targets with antiviral consequences. While investigations of anti-influenza iminosugar activities have been conducted since the 1980s, recent successes of nojirimycin derivatives have re-invigorated investigation of the therapeutic potential of iminosugars as orally available, low cytotoxicity, effective anti-influenza drugs.     

Antiviral agents active against human herpesviruses HHV-6, HHV-7 and HHV-8

A series of antiviral compounds were examined for their activity against human herpesvirus type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8). They were selected either because they are already approved for clinical use in the treatment of herpesvirus infections (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, brivudin, foscarnet and cidofovir) or have demonstrated marked activity against herpesviruses (lobucavir, H2G, A‒5021, D /L -cyclohexenyl G and S2242). In view of their host cell specificity, different cells and assays had to be used for determining antiviral activity against these three viruses. The most potent compounds with the highest antiviral selectivity index were: (i) for HHV-6; foscarnet, S2242, A-5021 and cidofovir; (ii) for HHV-7; S2242, cidofovir and foscarnet; and (iii) for HHV-8; S2242, cidofovir and ganciclovir. As mycophenolic acid has been shown to enhance significantly the activity of acyclic guanosine analogues (such as acyclovir, penciclovir and ganciclovir) in vitro against HSV-1, HSV-2, VZV and HCMV, it would seem worth evaluating whether mycophenolic acid also potentiates the activity of these acyclic guanosine analogues against HHV-6, -7 and -8. Copyright © 2001 John Wiley & Sons, Ltd.     

Preparation and Characterization of TAM-Loaded HPMC/PAN Composite Fibers for Improving Drug-Release Profiles

The present paper reports the preparation and characterization of composite hydroxypropyl methylcellulose/polyacrylonitrile (HPMC/PAN)-medicated fibers via a wet spinning technique. Tamoxifen (TAM) was selected as a model drug. Numerous analyses were conducted to characterize the mechanical, structure and morphology properties of the composite fibers. The drug content and in vitro dissolution behavior were also investigated. SEM images showed that the TAM-loaded HPMC/PAN composite fibers had a finger-like outer skin and a porous structure. FT-IR spectra demonstrated that there was a good compatibility between polymer and drug. Results from X-ray diffraction and DSC suggested that most of the incorporated TAM was evenly distributed in the fiber matrix in an amorphous state, except for a minority that aggregated on the surface of fibers. The drug content in the fibers was lower than that in the spinning solution and about 10% of TAM was lost during spinning process. In vitro dissolution results indicated that, compared to TAM–PAN fibers, HPMC/PAN composite systems had weaker initial burst release effects and more drug-loading. The combination of hydrophilic polymer HPMC with PAN could improve the performance of polymer matrix composite fibers in regulating the drug-release profiles.     

Synthesis and characterization of thermosensitive chitosan copolymer as a novel biomaterial

Novel water-soluble thermosensitive chitosan copolymers were prepared by graft polymerization of N-isopropylacrylamide (NIPAAm) onto chitosan using cerium ammonium nitrate (CAN) as an initiator. The physicochemical properties of the resulting chitosan-g-NIPAAm copolymers were characterized by Fourier transform infrared (FT-IR) spectroscopy, ¹H-nuclear magnetic resonance, X-ray diffraction measurement, thermogravimetric analysis (TGA) and solubility test. Sol–gel transition behavior was investigated by the cloud point measurement of the chitosan-g-NIPAAm aqueous solution. The gelling temperature was examined using the vial inversion method. The percentage of grafting (%) and efficiency of grafting (%) were investigated according to concentrations of monomer and initiator. The maximum grafted chitosan copolymer was obtained with 0.4 M NIPAAm and 6×10^-3 M CAN. Water-soluble chitosan-g-NIPAAm copolymers were prepared successfully and they formed thermally reversible hydrogel, which exhibits a lower critical solution temperature (LCST) around 32°C in aqueous solutions. A preliminary in vitro cell study showed nontoxic and bio- compatible properties. These results suggest that chitosan-g-NIPAAm copolymer could be very useful in biomedical and pharmaceutical applications as an injectable material for cell and drug delivery.     

Replication of HSV-1 in murine peritoneal macrophages: Comparison of various virus strains with different properties

Summary Thein vitro replication of eleven different strains of herpes simplex virus type 1 was studied in resident or thioglycollate-stimulated mouse macrophages. The strains of herpes simplex virus differed in the type of cytopathic effect, induction capacity for herpes simplex virus coded thymidine kinase and pathogenicity in the mouse. Herpes simplex virus replicated better in thioglycollate-stimulated macrophages than in resident macrophages.In vitro ageing of macrophages increased their replicative potency. Herpes simplex virus replicated better in macrophages from homozygous bg/bg C57/BL6J mice than in macrophages from their heterozygous littermates. Separation of macrophages on discontinous Percoll-gradients revealed 4 fractions with identical potency for replication. The ability of herpesvirus to replicate in macrophages varied from strain to strain of virus i.e. Wal > Len, clone 4 of Len, >L3-2s, JES, Ang^–, Ang⁺path, clone 2 of Len and >MDK clones. The ability to cause cytopathology also varied. Only strains Ang^– and Ang⁺path showed limited or late cytopathology in macrophages. The cell-fusing property of herpes simplex virus appeared to be more closely correlated with lower replication rates than production cell rounding. Thymidine kinase^– viruses replicated less well than thymidine kinase⁺ or thymidine kinase⁽⁺⁾ strains. Strains of herpes simplex virus with high or low pathogenicity for mice replicated in macrophages to the same degree. The phagocytic activity of macrophages for IgM-coated sheep red blood cells was inhibited earlier by strains of herpes simplex virus of type 2 than by strains of herpes simplex virus of type 1.With 4 FiguresIn partial fullfilment of the requirements for the M.D. degree.     

Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems

To develop more potent and convenient mucosal human papillomavirus (HPV) vaccines, we tested the effect of thermosensitive mucoadhesive vaginal vaccine delivery systems on the local and systemic antibody responses to HPV 16 L1 virus-like particles (VLP). HPV 16 L1 VLP expressed from recombinant baculovirus-infected Sf21 insect cells were delivered in phosphate-buffered saline (PBS) or thermosensitive mucoadhesive delivery systems, composed of poloxamers (Pol) and varying amounts of polyethylene oxide (PEO). Pol/PEO-based vaginal vaccine delivery systems existed in liquid form at room temperature, but gelled at 37 degrees C. The mucoadhesiveness of Pol/PEO-based delivery systems increased with PEO, but the formulations with PEO higher than 1.0% were too viscous to be administered into the vagina. Vaccine vehicles affected the vaginal and salivary immune responses to HPV 16 L1 VLP intravaginally administered into mice. At 42 days after the first intravaginal immunization of HPV 16 L1 VLP with cholera toxin, vaginal and salivary IgA titers were the highest in the group given in Pol/PEO 1.0% vehicle followed by Pol/PEO 0.4% and PBS vehicles. Intravaginal coadministration of HPV 16 L1 VLP and cholera toxin in Pol/PEO 1.0% showed 31- and 39-fold higher titers compared to the PBS-based HPV 16 L1 VLP groups administered by intravaginal and intramuscular routes, respectively. Following intravaginal administration, Pol/PEO 1.0%, but not Pol/PEO 0.4%, showed significantly higher HPV 16 L1 VLP-specific serum IgG titers as compared to the PBS vehicle. Our results indicate that the use of in situ-gelling vaginal vaccine delivery systems with increased mucoadhesiveness would be beneficial for more effective induction of mucosal and systemic immune responses to intravaginally administered HPV 16 L1 VLP vaccines.     

Evaluation of Antiviral Activities of Four Local Malaysian Phyllanthus Species against Herpes Simplex Viruses and Possible Antiviral Target

Nucleoside analogues such as acyclovir are effective antiviral drugs against herpes simplex virus infections since its introduction. However, with the emergence of acyclovir-resistant HSV strains particularly in immunocompromised patients, there is a need to develop an alternative antiherpetic drug and plants could be the potential lead. In this study, the antiviral activity of the aqueous extract of four Phyllanthus species were evaluated against herpes simplex virus type-1 (HSV-1) and HSV-2 in Vero cells by quantitative PCR. The protein expressions of untreated and treated infected Vero cells were studied by 2D-gel electrophoresis and Western blot. This is the first study that reported the antiviral activity of P. watsonii. P. urinaria was shown to demonstrate the strongest antiviral activity against HSV-1 and HSV-2, with SI >33.6. Time-of-addition studies suggested that the extract may act against the early infection stage and the replication stage. Protein expression studies indicated that cellular proteins that are involved in maintaining cytoskeletal structure could be potential target for development of antiviral drugs. Preliminary findings indicated that P. urinaria demonstrated potent inhibitory activity against HSV. Hence, further studies such as in vivo evaluation are required for the development of effective antiherpetic drug.     

The first immunoglobulin-like domain of porcine nectin-1 is sufficient to confer resistance to pseudorabies virus infection in transgenic mice

Summary. Nectin-1 is an alphaherpesvirus receptor that binds to virion glycoprotein D (gD). Porcine nectin-1 mediates entry of pseudorabies virus (PRV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), and bovine herpesvirus type 1 (BHV-1). The gD-binding domain of nectin-1 is the first or N-terminal immunoglobulin (Ig)-like domain of the entire ectodomain. Here, we generated three transgenic mouse lines expressing a fusion protein consisting of the first Ig-like domain of porcine nectin-1 and the Fc portion of porcine IgG1 to assess the antiviral potential of the first Ig-like domain of nectin-1 in vivo. All of the transgenic mouse lines showed significant resistance to PRV infection via intraperitoneal inoculation (survival rates of 67% to 100%). In the intranasal challenge, a lower but still significant protection was observed; 21% to 55% of the animals from the three transgenic mouse lines survived. The present results demonstrate that a soluble form of the first domain of porcine nectin-1 is able to exert a significant antiviral effect against pseudorabies virus infection.     

Topical application of polyethylenimine as a candidate for novel prophylactic therapeutics against genital herpes caused by herpes simplex virus

Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause genital herpes, which can enhance the acquisition of human immunodeficiency virus. The development of anti-HSV agents with novel mechanisms of action is urgently required in the topical therapy of genital herpes. In this study, the in vitro and in vivo anti-HSV effects of Epomin SP-012^®, a highly cationic polyethylenimine, were evaluated. When the in vitro antiviral effects of SP-012 were assessed, this compound showed potent activity against HSV-1 and HSV-2. It inhibited the attachment of HSV-2 to host cells and cell-to-cell spread of infection in a concentration-dependent manner and exerted a virucidal effect. No SP-012-resistant HSV-2 was found when the virus was successively passaged in the presence of SP-012. In a mouse genital herpes model, topically administered SP-012 inhibited the progression of the disease caused by HSV infection. These data illustrate that SP-012 may be a novel class of HSV inhibitor that would be acceptable for long-term topical application.     

ORIGINAL ARTICLE: Female Genital Tract Secretions Inhibit Herpes Simplex Virus Infection: Correlation with Soluble Mucosal Immune Mediators and Impact of Hormonal Contraception

Citation Shust GF, Cho S, Kim M, Madan RP, Guzman EM, Pollack M, Epstein J, Cohen HW, Keller MJ, Herold BC. Female genital tract secretions inhibit herpes simplex virus infection: correlation with soluble mucosal immune mediators and impact of hormonal contraception. Am J Reprod Immunol 2010; 63: 110–119 Problem Female genital tract secretions inhibit herpes simplex virus (HSV) infection, however, the intra‐ and inter‐subject variability, contribution of specific mediators, and impact of reproductive hormones have not been defined. Method of study Cervicovaginal lavage (CVL) (n = 89) obtained from nine cyclers and seven women on hormonal contraception (HC), who completed between three and eight weekly visits, were examined for anti‐herpes simplex virus activity and concentrations of mediators. Results The CVL inhibited HSV infection by a mean value of approximately 57% during the follicular or luteal phase, but only by 36% in hormonal contraceptive users. Human neutrophil peptides 1–3 (HNP1‐3) (P = 0.03), IL‐8 (P = 0.003), lactoferrin (P = 0.005), lysozyme (P = 0.003), IgA (P = 0.002), and IgG (P = 0.02) correlated with antiviral activity. Intra‐subject and inter‐subject variability was observed, suggesting that factors other than hormones contribute to innate defense. Conclusion Endogenous antimicrobial activity may provide a biomarker of healthy mucosal immunity and may be reduced in the setting of HC. However, larger prospective studies are needed.     

A chlorophyll c2 analogue from the marine brown alga <Emphasis Type="Italic">Eisenia bicyclis</Emphasis> inactivates the infectious hematopoietic necrosis virus,a fish rhabdovirus

Summary. We screened in vitro antiviral activity against a salmonid pathogenic virus, infectious hematopoietic necrosis virus (IHNV), from the extracts of a total of 342 species of marine algae collected from the Japanese coastline. The anti-IHNV activity was found primarily in MeOH extracts, and the extract from one marine brown alga in particular, Eisenia bicyclis, showed high anti-IHNV activity. The anti-IHNV compound was isolated and purified as MC15 from the E. bicyclis extract, and the chemical structure was determined by several spectrometric analyses. The antiviral compound was proved to be a chlorophyll c2 derivative lacking the metal ion Mg²⁺. MC15 showed similar antiviral activity against other salmonid enveloped viruses such as Paralichthys olivaceus virus and Oncorhynchus masou virus, and stability against any pH and temperatures up to 100 °C. No cytotoxicity was observed at up to 5 μg/ml. The antiviral mechanism of MC15 appears to be direct inactivation of the viral particles. A time course study showed that the inactivation of IHNV was completed within 40 min when 200 PFU of IHNV was reacted with MC15 at 800 ng/ml.     

Situational antiviral drug prophylaxis for HSV type 1 recurrences

Recurrent herpes simplex virus type 1 infection is generally associated with mild morbidity. However, frequent recurrences may have a significant psychosocial impact, and reactivation in certain high-risk situations may cause considerable morbidity. Controlled trials demonstrate that antiviral drug prophylaxis can be efficacious in selected circumstances; even for other situations, clinical reports suggest that such antiviral drug prophylaxis remains effective.