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Antiviral Research (v.93, #2)

Inside Back Cover: Notes to Authors (pp. ibc).

Prelim II: Editorial Board (pp. ii).

Modulation of the immunogenicity of virus-like particles composed of mutant hepatitis B virus envelope subunits by Wan-Shoo Cheong; Michiko Hyakumura; Lilly Yuen; Nadia Warner; Stephen Locarnini; Hans J. Netter (pp. 209-218).

► Mutant hepatitis B envelope proteins (HBsAgS) with cysteine substitutions generated. ► Non-native virus-like particles (VLPs) assembled by mutant HBsAgS subunits. ► Changes in disulfide bonding modulate VLP immunogenicity. ► Non-native VLPs induce enhanced cellular immune response. ► Cys residues conserved: possibly contributing to a structure to reduce immunogenicity.Virus-like particles (VLPs) are non-infectious subviral protein complexes, which possess structural features identical or closely related to infectious virions. They are utilized as delivery tools for immunologically relevant antigenic sequences. In order to investigate whether mutant subunits can modulate the VLP immunogenicity, comparative immunization studies with wild-type and non-native VLPs were performed. To determine whether disulfide bonding impacts on the immunogenicity of hepatitis B virus envelope proteins (HBsAg), mutant HBsAg subunits with single, double and triple cysteine residue substitutions were generated. The mutant proteins were expressed in cell culture, secretion competent non-native VLPs generated, followed by immunization studies in mice to measure the cellular immune response. The reduced ability of mutant HBsAg proteins to form disulfide bonds does not interfere with their ability to assemble into secretion competent VLPs. Depending on specific cysteine to alanine changes, VLPs could be generated with or without an increased ratio of monomeric versus dimeric/oligomeric subunits compared to wild-type VLPs. The utilization of non-native VLPs resulted in enhanced cellular immune responses and does not seem to depend on the ratio between monomeric or dimeric/oligomeric subunits. Comparative immunization studies strongly indicate that changes in the disulfide bonding modulate the VLP immunogenicity most likely due to structural changes. We hypothesize that structural features have evolved with reduced immunogenicity to evade the constraints imposed by the immune system. Altering VLP conformation may represent an attractive strategy to modulate antigen processing resulting in an enhanced immune response and/or a changed hierarchy of epitope presentation.

Keywords: Hepatitis B virus; Virus-like particle; Immunogenicity; Vaccination study

Activity of ultra-low doses of antibodies to gamma-interferon against lethal influenza A(H1N1)2009 virus infection in mice by Sergey A. Tarasov; Vladimir V. Zarubaev; Evgeniy A. Gorbunov; Svetlana A. Sergeeva; Oleg I. Epstein (pp. 219-224).

► Application of antibodies to gamma-interferon results in protection from lethal influenza. ► Antibodies to gamma-interferon decrease the replication of influenza virus in the lungs. ► Lung architecture at the foci of viral pneumonia is improved after application of antibodies to gamma-interferon.The influenza A virus is a highly infective agent that causes acute pulmonary diseases. In serious cases, it causes pneumonia which is particularly fatal in patients with cardiopulmonary diseases, obesity, young children and elderly people. The present study shows a protective effect of ultra-low doses of purified antibodies to gamma-interferon (Anaferon for children®, AC®) against lethal influenza virus infection caused by pandemic influenza virus A(H1N1) in mice.Balb/c mice were infected with mouse-adapted pandemic influenza virus A/California/07/09 (H1N1)v. Mortality, weight loss, infectious titer of the virus in lungs and lung morphology were monitored in the groups of AC®-, oseltamivir- and placebo-treated animals.The protective action of AC® was demonstrated by prolongation of life of the infected animals, reduction of infectious titer of the virus in the lung tissue, normalization of weight dynamics in the course of disease, decrease in mortality of treated animals compared to a placebo control and normalization of lung tissue structure. The protective activity of AC® was similar to that of the reference compound oseltamivir. Combination of AC® with oseltamivir resulted in a higher protective effect comparing to oseltamivir alone.Based on the results obtained, AC® should be considered as an important part of anti-influenza prophylaxis and therapy, in particular in severe cases of the disease.

Keywords: Influenza; Pandemic; Antibodies to interferon; Antiviral activity

Inactivation of high and low pathogenic avian influenza virus H5 subtypes by copper ions incorporated in zeolite-textile materials by Kunitoshi Imai; Haruko Ogawa; Vuong Nghia Bui; Hiroshi Inoue; Jiro Fukuda; Masayoshi Ohba; Yu Yamamoto; Kikuyasu Nakamura (pp. 225-233).

The effect of cotton textiles containing Cu²⁺ held by zeolites (CuZeo-textile) on the inactivation of H5 subtype viruses was examined. Allantoic fluid (AF) containing a virus (AF virus) (0.1ml) was applied to the textile (3×3-cm), and incubated for a specific period at ambient temperature. After each incubation, 0.9ml of culture medium was added followed by squeezing to recover the virus into the medium. The recovered virus was titrated using Madin–Darby canine kidney (MDCK) cells or 10-day-old embryonated chicken eggs.The highly pathogenic H5N1 and the low pathogenic H5N3 viruses were inactivated on the CuZeo-textile, even after short incubation. The titer of A/chicken/Yamaguchi/7/04 (H5N1) in MDCK cells and in eggs declined by >5.0 log₁₀ and 5.0log₁₀, respectively, in 30s. The titer of A/whooper swan/Hokkaido/1/08 (H5N1) in MDCK cells declined by 2.3 and 3.5 in 1 and 5min, respectively. When A/whistling swan/Shimane/499/83 (H5N3) was treated on the CuZeo-textile for 10min, the titer declined by >5.0log₁₀ in MDCK cells and by >3.5log₁₀ in eggs. In contrast, no decrease in the titers was observed on cotton textiles containing zeolites alone (Zeo-textile). Neither cytopathic effects nor NP antigens were detected in MDCK cells inoculated with the H5N1 virus treated on the CuZeo-textile. The viral genes (H5, N1, M, and NP) were amplified from the virus treated on the CuZeo-textile by RT-PCR. The hemagglutinating activity of the CuZeo-textile treated virus was unaffected, indicating that virus–receptor interactions were maintained. Electron microscopic analysis revealed a small number of particles with morphological abnormalities in the H5N3 virus samples recovered immediately from the CuZeo-textile, while no particles were detectable in the 10-min treated sample, suggesting the rapid destruction of virions by the Cu²⁺ in the CuZeo-textile. The loss of infectivity of H5 viruses could, therefore, be due to the destruction of virions by Cu²⁺. Interestingly, CuCl₂ treatment (500 and 5000μM) did not have an antiviral effect on the AF viruses (H5N1 and H5N3) even after 48h of incubation, although the titer of the purified H5N3 virus treated with CuCl₂ declined greatly. The antiviral effect was inhibited by adding the AF to the purified H5N3 virus prior to the CuCl₂ treatment. The known antibacterial/antifungal activities of copper suggest that the CuZeo-textile can be applied at a high level of hygiene in both animals and humans.

Keywords: Avian influenza virus; H5 subtype; Copper ion; Zeolite; Antiviral effect

Evaluation of the antiviral activity of (1′S,2′R)-9-[[1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl]guanine (A-5021) against equine herpesvirus type 1 in cell monolayers and equine nasal mucosal explants by Sarah Glorieux; Annelies P. Vandekerckhove; Nesya Goris; Xiao-Yun Yang; Lennert Steukers; Gerlinde R. Van de Walle; Siska Croubels; Johan Neyts; Hans J. Nauwynck (pp. 234-238).

► Anti-EHV1 activity of A-5021 was tested in EEL cells and equine nasal explants. ► A-5021 proves about 15-fold more potent than acyclovir in EEL cells. ► Contrary to acyclovir, A-5021 completely inhibits EHV1 plaque formation in explants. ► A-5021 is a potent inhibitor of EHV1 replication.Equine herpesvirus 1 (EHV1) is a ubiquitous equine alphaherpesvirus that causes respiratory disease, neurological symptoms and abortions. Current vaccines are not fully protective and effective therapeutics are lacking. A-5021 [(1′S,2′R)-9-[[1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl]guanine], previously shown to possess potent anti-herpetic activity against most human herpesviruses, was evaluated for its potential to inhibit EHV1 replication. In equine embryonic lung (EEL) cells, infected with either a non-neurovirulent (97P70) or a neurovirulent (03P37) EHV1 isolate, A-5021 proved to be about 15-fold more potent than acyclovir in inhibiting viral replication. Moreover, in equine nasal mucosal explants, A-5021 (at 8 and 32μM) was able to completely inhibit viral plaque formation whereas acyclovir did not exert an antiviral effect at these concentrations. Our data demonstrate that A-5021 is a potent inhibitor of EHV1 replication and may have potential for the treatment and/or prophylaxis of infections with this virus.

Keywords: Equine herpesvirus 1 (EHV1); Antiviral compound A-5021; Equine nasal explant study

Host interleukin-28B genetic variants versus viral kinetics in determining responses to standard-of-care for Asians with hepatitis C genotype 1 by Chung-Feng Huang; Ming-Lun Yeh; Jee-Fu Huang; Jeng-Fu Yang; Ming-Yen Hsieh; Zu-Yau Lin; Shinn-Cherng Chen; Liang-Yen Wang; Edward Hsi; Suh-Hang Hank Juo; Chia-Yen Dai; Wan-Long Chuang; Ming-Lung Yu (pp. 239-244).

► The IL-28B genetic variant is the most important predictor of attaining a RVR. ► RVR is the most important factor for an SVR irrespective of host IL-28B genotype. ► The effect of IL-28B gene was restricted to non-RVR/high viral loads patients. ► CEVR is the only determinant for non-RVR patients regardless IL-28B genes. ► Changes of viral kinetics overweight host IL-28 genetic variants for HCV-1.Both interleukin-28B genetic variants and on-treatment virological responses are factors predictive of treatment outcome in hepatitis C virus genotype 1 (HCV-1) patients. We aimed to compare the clinical significance of the two factors.Rs8099917 genotype and on-treatment responses were determined in 182 HCV-1 patients with 48-week peginterferon/ribavirin.Comparing to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, 46.2% vs. 19.2%, P=0.01) and sustained virological response (SVR, 85.3% vs. 42.3%, P<0.001) rates. Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/95% confidence intervals [OR/CI]: 4.25/1.39-13.01). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 57.22/6.23-525.37), followed by the carriage of rs8099917 TT genotype (OR/CI: 10.06/3.12-32.44). However, while on-treatment factors were taken into account, the cEVR was the most important determinant to an SVR (OR/CI:54.98/9.07-333.38), whereas the influence of rs8099917 genotype became non-significant in non-RVR patients.Rs8099917 TT genotype is significantly independently predictive of on-treatment virological responses, which were the major determinants of an SVR, in Asian HCV-1 patients.

Keywords: Abbreviations; ALT; alanine aminotransferase; AST; aspartate aminotransferase; APRI; the aspartate aminotransferase-to-platelet ratio index; CHC; chronic hepatitis C; EOTVR; end-of-treatment virological response; GWAS; genome-wide associated studies; HCV; hepatitis C virus; IL-28B; interleukin 28B; NPV; negative predictive value; PPV; positive predictive value; RVR; rapid virological response; SNP; single nucleotide polymorphism; SVR; sustained virological responseIL-28B; RVR; cEVR; HCV-1; Treatment

Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors by Suzanne M. Tomlinson; Stanley J. Watowich (pp. 245-252).

► Presents efficiency improvements to conventional biochemical HTS. ► Parallel HTS enabled discovery of promising DENV and WNV protease inhibitors. ► Kinetic validation showed competitive and mixed noncompetitive inhibition mechanism. ► Inhibitors were specific for the flavivirus serine proteases. ► Of interest to pharmaceutical and academic researchers in antiviral drug discovery.Dengue virus (DENV), a mosquito-borne member of the family Flaviviridae, is a significant global pathogen affecting primarily tropical and subtropical regions of the world and placing tremendous burden on the limited medical infrastructure that exists in many of the developing countries located within these regions. Recent outbreaks in developed countries, including Australia (), France (), Taiwan (), and the USA (), lead many researchers to believe that continued emergence into more temperate latitudes is likely. A primary concern is that there are no approved vaccines or antiviral therapies to treat DENV infections. Since the viral NS2B-NS3 protease (DENV NS2B-NS3pro) is required for virus replication, it provides a strategic target for the development of antiviral drugs. In this study, proof-of-concept high-throughput screenings (HTSs) were performed to unambiguously identify dengue 2 virus (DEN2V) NS2B-NS3pro inhibitors from a library of 2000 compounds. Validation screens were performed in parallel to concurrently eliminate insoluble, auto-fluorescing, and/or nonspecific inhibitors. Kinetic analyses of the hits revealed that parallel substrate fluorophore (AMC) interference controls and trypsin inhibition controls were able to reduce false positive rates due to solubility and fluorophore interference while the trypsin inhibition control additionally eliminated non-specific inhibitors. We identified five DEN2V NS2B-NS3pro inhibitors that also inhibited the related West Nile virus (WNV) protease (NS2B-NS3pro), but did not inhibit the trypsin protease. Biochemical analyses revealed various mechanisms of inhibition including competitive and mixed noncompetitive inhibition, with the lowest K_i values being 12±1.5μM for DEN2V NS2B-NS3pro and 2±0.2μM for WNV NS2B-NS3pro.

Keywords: Dengue virus; West Nile virus; NS2B-NS3; Protease; Inhibitors; High-throughput screen

In vitro inhibition of influenza A virus infection by marine microalga-derived sulfated polysaccharide p-KG03 by Meehyein Kim; Joung Han Yim; So-Yeon Kim; Hae Soo Kim; Woo Ghil Lee; Sung Jin Kim; Pil-Sung Kang; Chong-Kyo Lee (pp. 253-259).

► The sulfated polysaccharide p-KG03 is derived from red marine microalga. ► It is active against influenza A virus but not all influenza B virus in vitro. ► The antiviral activity is highly correlated with its affinity to viral particles. ► The main mode of action of p-KG03 is to interfere with viral entry into cells.The sulfated polysaccharide, p-KG03, purified from the marine microalga, Gyrodinium impudium, is a unique compound comprising homogenous galactose units conjugated to uronic acid and sulfated groups. Although previous studies showed that p-KG03 suppresses tumor cell growth and infection by encephalomyocarditis virus, its effect against enveloped virus infection and the biological mechanism of action have not been elucidated. In this report, the inhibitory activity of p-KG03 against influenza virus was examined and compared with that of other sulfated polysaccharides (fucoidan and pentosan polysulfate) and antiviral agents (oseltamivir phosphate, oseltamivir carboxylate, amantadine, and ribavirin). The results of a cytopathic effect reduction assay using MDCK cells demonstrated that p-KG03 exhibited the 50% effective concentration (EC₅₀) values of 0.19–0.48μg/ml against influenza type A virus infection (selectivity index >200) but not all influenza type B viruses. Mechanism studies showed that inhibition of influenza virus replication was maximized when p-KG03 was added during or within 6h after viral infection, suggesting that mainly the viral adsorption and internalization steps are targeted by this compound. The results of influenza virus binding assay to p-KG03 and fluorescence microscopy indicate that the antiviral activity of p-KG03 is directly associated with its interaction with viral particles. The sulfated polysaccharide p-KG03 is a potent and specific influenza A viral entry inhibitor and may be a candidate for antiviral drug development.

Keywords: Influenza virus; Sulfated polysaccharide; Marine alga; Anti-influenza viral agent; Virus entry inhibitor

The development of Chinese specific human cytomegalovirus polyepitope recombinant vaccine by Ping Zhao; Dao-Xin Ma; Shuang Yu; Fu-Zhong Xue; Wei-Wei Zhu; Na Shao; Jing-Ru Zhang; Chun-Yan Ji (pp. 260-269).

► HCMV disease remains a major obstacle for organ transplants. ► Epitope-based vaccine becomes an effective approach to prevent HCMV infection. ► A novel polyepitope vaccine in this study can cover 92% of Chinese population. ► This vaccine was proved to have specific and vigorous immunological response for HCMV.Human cytomegalovirus (HCMV) infection is a major cause of morbidity in the recipients of organ transplants and in the congenitally infected infants. HCMV vaccine has emerged as an effective approach to prevent HCMV infection particularly for the development of multiple viral antigens vaccination and human leukocyte antigen (HLA)-restricted polyepitope technology. As the Chinese population makes up more than one fifth of the population worldwide, it is important to develop HCMV vaccines more specific for the Chinese population by targeting Chinese-restricted HLA alleles and antigens. In the present study, we designed a novel chimeric polyepitope vaccine based on the replication-deficient adenovirus Ad5F35, which encodes 83 HCMV T cell epitopes from 15 different HCMV antigens, restricted to 14 HLA I and 7 HLA II alleles that cover 92% of the Chinese population. Our results show that the recombinant adenovirus vaccine Ad5F35-CTL·Th can be efficiently transfected and expressed in peripheral blood mononuclear cells (PBMCs) with little cytopathic activity. Ad5F35-CTL·Th can also be endogenously processed and presented by PBMCs. Ad5F35-CTL·Th-stimulated HCMV-specific cytotoxic T lymphocytes (CTLs) showed strong cytolytic activity against HCMV polyepitope-sensitized target cells. The CTL activity was accompanied by high levels of IFN-γ production after Ad5F35-CTL·Th stimulation. The specificity and vigorous response to the recombinant adenovirus vaccine in vitro makes it a potential candidate to be used for transplantation recipients or congenitally infected infants.

Keywords: Human cytomegalovirus (HCMV); Vaccine; Chinese; HLA; Immunotherapy

MiR-342-5p suppresses coxsackievirus B3 biosynthesis by targeting the 2C-coding region by Linlin Wang; Ying Qin; Lei Tong; Shuo Wu; Qiang Wang; Qingguo Jiao; Zhiwei Guo; Lexun Lin; Ruixue Wang; Wenran Zhao; Zhaohua Zhong (pp. 270-279).

► miR-342-5p can inhibit the biosynthesis of coxsackievirus B3. ► The target of miR-342-5p locate at the 2C-coding region of coxsackievirus B3. ► miR-342-5p is a potential therapeutic agent against CVB3 infection.Coxsackievirus B type 3 (CVB3) is one of the major pathogens associated with human heart disease. miRNAs are a class of short, noncoding RNA that can post-transcriptionally modulate gene expression. By comparing the CVB3 genome and miR-342-5p sequences, we found there were potential miR-342-5p targets in the CVB3 genome. To verify the effect of miR-342-5p on CVB3 biosynthesis, HeLa cells were infected with a Renilla luciferase (RLuc)-expressing CVB3 variant (RLuc-CVB3). We observed that miR-342-5p could significantly inhibit the expression of RLuc in infected cells. In HeLa cells infected with an enhanced green fluorescence protein (EGFP)-expressing CVB3 variant (EGFP-CVB3), EGFP expression was also significantly inhibited by miR-342-5p. The inhibitory effect of miR-342-5p on EGFP expression in EGFP-CVB3-infected cells could be reversed by transfection with anti-miR-342-5p oligonucleotide (AMO-miR-342-5p). Moreover, RNA and protein biosynthesis in wild-type CVB3 was significantly inhibited by miR-342-5p. By mutating the putative targets of miR-342-5p in the 2C-coding region, a sequence, nt4989–nt5015, was identified as the miR-342-5p target. The conserved nt4989–nt5015 sequences of CVB type 1–5 suggest miR-342-5p may exert its inhibitory effect in other types of coxsackievirus besides CVB3. Western blotting indicated that miR-342-5p could indeed suppress protein expression in CVB type 1 and 5. There was a moderate abundance of miR-342-5p in the gut, heart, and brain of Balb/c mice, suggesting that miR-342-5p may interact with CVB3 in vivo. Taken together, these results indicate that miR-342-5p can inhibit CVB3 biosynthesis by targeting its 2C-coding region and therefore may be a potential therapeutic agent in the treatment of CVB3 infection.

Keywords: MiR-342-5p; Coxsackievirus B3; Biosynthesis; 2C-coding region; Antiviral activity

Novel antivirals inhibit early steps in HPV infection by Hao-Shun Huang; Dohun Pyeon; Shane M. Pearce; Simon M. Lank; Laura M. Griffin; Paul Ahlquist; Paul F. Lambert (pp. 280-287).

► HPVs are common sexually transmitted pathogens that cause various human cancers. ► In this study, we identify novel, small molecule inhibitors of HPV infection. ► Lead inhibitors have sub-micromolar IC₅₀s and little to no cytotoxicity. ► They also display a broad range of effectiveness against multiple HPV genotypes. ► These compounds represent new microbicides for preventing HPV infection.The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC₅₀’s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12h following infection. Twenty-nine #13-like and 15 #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post-entry.

Keywords: High throughput screen; Papillomavirus; Entry; Pseudovirus

In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4 by Nicolas A. Margot; Rebecca M. Hluhanich; Gregg S. Jones; Kristen N. Andreatta; Manuel Tsiang; Damian J. McColl; Kirsten L. White; Michael D. Miller (pp. 288-296).

► Elvitegravir is an HIV-1 integrase strand transfer inhibitor in phase 3 clinical testing. ► Two metabolites (M1 and M4) of EVG are found at low level in EVG-treated subjects. ► We conducted resistance selection and cross-resistance analyses of M1 and M4 in vitro. ► We found that the resistance profiles of M1 and M4 overlap with that of EVG. ► Therefore, M1 and M4 are unlikely to alter the resistance profile of EVG in the clinic.Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross-resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant.

Keywords: HIV; Integrase inhibitor; Resistance selection

Evaluation of susceptibility locus for response to interferon-α based therapy in chronic hepatitis B patients in Chinese by Xiaopan Wu; Zhenhui Xin; Xilin Zhu; Liping Pan; Zhuo Li; Hui Li; Ying Liu (pp. 297-300).

► This retrospective nested case-control study include 512 HBeAg positive CHB patients. ► We aim to see if SNP in IL28B is associated with therapy efficacy of IFNα. ► The G allele of rs8099917 is associated with higher rate of response.In 2009, three independent genome-wide association studies reported that genetic variation in the interleukin 28B gene to be associated with the response to interferon-α/ribavirin therapy in hepatitis C virus genotype 1 infected patients. We carried out the present study to assess whether such polymorphisms also affect the therapy effect of another interferon-α responsive illness as chronic hepatitis B. Five hundred and twelve interferon-α treatment-naïve HBeAg seropositive chronic hepatitis B patients were enrolled in the present retrospective nested case-control study. All patients received PEG-IFN-α-2a based treatment and were examined for the therapy efficacy. SNP rs8099917 was genotyped using the MassArray system (Sequenom). Interestingly, the frequency of G allele of rs8099917 was significantly higher in response group than in non response group (8.3% vs. 3.9%, p=0.003, OR=0.44, 95%CI=0.25–0.79). The genotype distributions of this SNP also differed significantly between two groups ( p=0.003). Our study suggested that the G allele of rs8099917 was associated with higher rate of response in HBeAg seropositive chronic hepatitis B patients treated with interferon α.

Keywords: Chronic hepatitis B; Interferon-α therapy; Single nucleotide polymorphism; Interleukin 28B gene; Sustained virologic response

Efficacy of ASP2151, a helicase–primase inhibitor, against thymidine kinase-deficient herpes simplex virus type 2 infection in vitro and in vivo by Takehiro Himaki; Yumi Masui; Koji Chono; Tohru Daikoku; Masaya Takemoto; Bo Haixia; Tomoko Okuda; Hiroshi Suzuki; Kimiyasu Shiraki (pp. 301-304).

► A helicase–primase inhibitor of herpes virus, ASP2151, was characterized. ► ASP2151 showed anti-HSV activity in vitro and in vivo. ► ASP2151 inhibited the growth of acyclovir-resistant/TK-deficient HSV. ► ASP2151 showed therapeutic efficacy against TK-deficient HSV-2 infection in mice.ASP2151 was developed as a novel inhibitor of herpes simplex virus (HSV) and varicella-zoster virus helicase–primase. The anti-HSV activity of ASP2151 toward a clinical HSV isolate with acyclovir (ACV)-resistant/thymidine kinase (TK)-deficiency was characterized in vitro and in vivo using a plaque reduction assay and the ear pinna infection in mice. The IC₅₀ ranged from 0.018 to 0.024μg/ml, indicating the susceptibility of TK-deficient HSV-2 was similar to that of wild-type HSV-2 strains. Anti-HSV activity of ASP2151 in vivo was evaluated in mice infected with wild-type HSV-2 and TK-deficient HSV-2. ASP2151 significantly reduced the copy numbers of wild-type HSV-2 and TK-deficient HSV-2 at the inoculation ear pinna, while valacyclovir significantly reduced the copy number of wild type HSV-2 but not that of TK-deficient HSV-2 in the inoculated ear pinna. Thus, ASP 2151 showed therapeutic efficacy in mice infected with both wild-type and TK-deficient HSV-2. In conclusion, ASP2151 is a promising novel herpes helicase–primase inhibitor that indicates the feasibility of ASP2151 for clinical application for the treatment of HSV infections, including ACV-resistant/TK-deficient HSV infection.

Keywords: Herpes simplex viruses; Thymidine kinase; ASP2151; Helicase–primase inhibitor; Resistance; Acyclovir

Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone by Sharon E. Altmann; Alvin L. Smith; Julie Dyall; Reed F. Johnson; Lori E. Dodd; Peter B. Jahrling; Jason Paragas; Joseph E. Blaney (pp. 305-308).

► FDA-approved drug mitoxantrone had in vitro activity against cowpox and monkeypox. ► Mitoxantrone increased survival time and survival rate in C57Bl/6 mice infected intraperitoneally with cowpox. ► Mitoxantrone showed significant in vitro synergy with cidofovir against cowpox. ► No synergy was observed in vivo between mitoxantrone and cidofovir versus cowpox in intranasally-infected BALB/c mice. ► Fewer animals survived treatment with 0.5mg/kg MXN and 100mg/kg CDV compared to that dose of CDV alone.Mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. Mitoxantrone demonstrated an EC₅₀ of 0.25μM against cowpox and 0.8μM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy, mitoxantrone was tested for synergistic activity with cidofovir. In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5mg/kg mitoxantrone and 100mg/kg cidofovir than with 100mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model.

Keywords: Poxvirus; Mitoxantrone; Cowpox; Monkeypox; Synergy

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Antiviral Research (v.93, #2)