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Antiviral Research (v.69, #3)
A target on the move: Innate and adaptive immune escape strategies of hepatitis C virus by Robert Thimme; Volker Lohmann; Friedemann Weber (pp. 129-141).
Obligate intracellular parasites such as the hepatitis C virus (HCV) have to cope intensively with immune responses in order to establish persistent infection. Powerful antiviral mechanisms of the host act on several levels. The innate immune response is able to slow down viral replication and activate cytokines which trigger the synthesis of antiviral proteins. The adaptive immune system neutralizes virus particles and destroys infected cells. Viruses have therefore developed a number of countermeasures to stay moving targets for the immune system. Here, we attempt to summarize the current state of research regarding innate and adaptive immune responses against HCV and the different escape strategies evolved by this virus.
Keywords: Hepatitis C virus; Innate immunity; Interferon system; Adaptive immunity; Escape mechanisms
Are in vitro hepatitis B core promoter mutations important for clinical alterations in viral load? by Yan Cheng; Bee Leng Seet; Carmen Shair Ling Ong; Shanthi Wasser; Theresa May Chin Tan; Frank Josef Peter; Seng Gee Lim (pp. 142-151).
In vitro studies of HBV core promoter mutations in hepatoma cell lines suggest that some mutations in core promoter transcription factor binding sites result in reduced core promoter activity and viral replication. We sought to validate this hypothesis using clinical samples with viral load differences before and after HBeAg seroconversion. A consensus sequence for transcription factor binding sites/regulatory regions was constructed based on published studies. Serum from two time points in 33 seroconverters and 10 interferon non-responders (controls) were utilized. Genotyping, HBV DNA quantification and direct sequencing of core promoter were performed. There were 216 new mutations following HBeAg seroconversion but few in controls. Mutations or mismatches to consensus transcription factor/regulatory region sequences clustered at nucleotide positions appeared genotype-specific, non-group specific or baseline mismatches and were discounted as having significant impact on viral replication. Only a few mutations in three seroconverters (9.1%) were specific, while 39.4% had no new mutations that could be attributed to reduction in viral load following HBeAg seroconversion. In 51.5% of patients, mutations were of uncertain significance because they occurred in demonstrated non-critical clustered nucleotide positions. Core promoter mutations post-seroconversion did not correlate with in vitro induced mutations that reduced the promoter activity.
Keywords: Hepatitis B virus; Core promoter; Mutation; Transcription factors; Hepatitis B e antigen seroconversion
Rapid determination of antiviral drug susceptibility of herpes simplex virus types 1 and 2 by real-time PCR by Thuong Nguyen Thi; Claire Deback; Isabelle Malet; Pascale Bonnafous; Zaïna Ait-Arkoub; Henri Agut (pp. 152-157).
An antiviral drug susceptibility assay of herpes simplex virus (HSV) was developed using real-time PCR quantification of intracellular viral DNA load. The number of HSV DNA copies within Vero cells after 24h infection was strongly correlated with the number of plaques obtained after 72h infection. Antiviral drug susceptibility of HSV was determined after virus growth for 24h by measuring the reduction of intracellular HSV DNA in the presence of increasing concentrations of either acyclovir (ACV) or foscarnet (PFA). This assay required neither preliminary titration of infectious stock nor follow-up of cytopathic effect. The 50% inhibitory concentrations (IC50s) obtained with 27 isolates of HSV types 1 and 2 by using this test were significantly correlated with those obtained in parallel with plaque reduction assay taken as the reference method ( r=0.91, p<0.0001 and r=0.51, p=0.009 for ACV and PFA, respectively). The threshold real-time PCR IC50s for ACV and PFA resistance did not differ according to HSV type and were determined to be 1.0 and 100μM, respectively. The real-time PCR susceptibility assay reported here is rapid, reproducible, applicable for HSV-1 as well as HSV-2, and suitable for automation.
Keywords: Herpes simplex virus; Acyclovir; Foscarnet; Resistance; Real-time PCR
Pathogenicity and immunogenicity in mice of vaccinia viruses mutated in the viral envelope proteins A33R and B5R by Irina Gurt; Ihab Abdalrhman; Ehud Katz (pp. 158-164).
The pathogenicity and immunogenicity in mice of WR.cl and WR.c3, two mutants of the Western Reserve (WR) strain of vaccinia virus, mutated in the A33R and B5R proteins of the outer envelope of the virus, respectively, were studied. WR.c1 was the most attenuated virus, WR.c3 was somewhat more pathogenic, while WR was the most virulent of the three. While the WR and the WR.c3 viruses, intranasally inoculated into mice, spread efficiently to the different internal organs of the animal, including the brain, WR.c1 was restricted to the lungs only. Mice, intranasally infected with 500 plaque forming units of the WR, WR.c1, or WR.c3 viruses, were protected against infection with a lethal dose of the WR strain.
Keywords: Vaccinia virus; Mutants; Pathogenicity; Immunogenicity
Protective immunity against acute phleboviral infection elicited through immunostimulatory cationic liposome-DNA complexes by Brian B. Gowen; Jeff Fairman; Donald F. Smee; Min-Hui Wong; Kie-Hoon Jung; Anne M. Pace; Matthew L. Heiner; Kevin W. Bailey; Steven W. Dow; Robert W. Sidwell (pp. 165-172).
Cationic liposome-DNA complexes (CLDC) have been demonstrated to induce potent antitumor activities. The ability of these complexes to elicit protective immunity against viral infections has not been fully explored. Here we report findings on the use of CLDC as an antiviral agent in a mouse model of acute phleboviral (Punta Toro virus) disease. CLDC treatment of mice challenged with Punta Toro virus (PTV) resulted in dramatic increases in survival and reduced viral burden and other parameters indicative of protection against disease. CLDC were effective when administered by intraperitoneal and intravenous routes and elicited protective immunity when given within 1 day of virus challenge. Treatments administered 36h or longer after challenge, however, were not effective in preventing mortality or disease. CLDC treatment induced release of a number of potential antiviral cytokines including IFN-γ, IL-12, and IFN-α. Taken together, our findings indicate that non-specific immunotherapy with CLDC appears to be an effective treatment for blocking PTV-induced disease and suggests that further exploration in other viral disease models may be warranted.
Keywords: Liposome; Plasmid DNA; Innate immunity; Phlebovirus
Inhibition of human immunodeficiency virus type 1 infection in macrophages by an alpha-v integrin blocking antibody by Berta Bosch; Imma Clotet-Codina; Julià Blanco; Eduardo Pauls; Gemma Coma; Samandhy Cedeño; Francesc Mitjans; Anuska Llano; Margarita Bofill; Bonaventura Clotet; Jaume Piulats; José A. Esté (pp. 173-180).
Macrophages are key cells for HIV infection and HIV spreading inside the organism. Macrophages cultured in vitro can be successfully infected after differentiation with cytokines such as macrophage colony stimulating factor (M-CSF). In the monocyte to macrophage differentiation process with M-CSF, αv-integrins are upregulated concomitantly with the capacity of HIV to generate a productive virus infection. In the present study we show that an anti-αv antibody, 17E6, inhibited HIV-1 infection of primary macrophages. The effect of 17E6 on HIV-1 BaL replication in acutely infected macrophages was dose-dependent, with a 50% effective concentration (EC50) of 17±2μg/ml in the absence of cytotoxicity. Similarly, a monoclonal antibody targeting the αvβ6 integrin (14D9.F8) also inhibited HIV-1 BaL infection in this cell type. 17E6 reduced the detection of HIV-1 BaL proviral DNA in acutely infected macrophages, but was completely ineffective against HIV-1 BaL production in chronically infected macrophages, suggesting that 17E6 inhibited HIV infection at an early stage of the virus cycle. Finally, a small molecular weight antagonist of the αvβ6 integrin, EMD 409849, reduced HIV replication at subtoxic concentrations. Therefore, our results suggest that αv-containing integrins could play a role in HIV replication in macrophages and suggest that small-molecular-weight compounds might interfere with HIV replication in macrophages through the interaction with αv integrins.
Keywords: Macrophages; HIV-1; Integrins; alpha-v; Macrophage colony-stimulating factor; Anti-HIV agents
Amino acid insertions at position 35 of HIV-1 protease interfere with virus replication without modifying antiviral drug susceptibility by Stefania Paolucci; Fausto Baldanti; Luca Dossena; Giuseppe Gerna (pp. 181-185).
Among 1330 patients undergoing highly active antiretroviral therapy (HAART), 3 showed 1 or 2 amino acid (aa) insertions at position 35 of the HIV-1 protease gene. Protease genes containing aa insertions, either in the presence (ins35G+res.muts, ins35TN+res.muts) or absence (ins35G, ins35TN) of other resistance mutations, were introduced into the wild-type HIV-1 strain NL4-3. The introduction of ins35G and ins35TN in the wild-type protease confirmed that these mutations were per se not responsible of decreased drug susceptibility. The replication rate of mutant recombinant viruses was determined by HIV RNA quantification in supernatants of cell cultures in comparison with a recombinant HIV-1 strain with wild-type protease. Recombinant ins35G and ins35TN HIV-1 strains did not display increased resistance to currently used protease inhibitors (PIs). Comparison of ins35TN+res.muts and ins35G+res.muts with respect to the corresponding recombinant rescue mutants showed that ins35TN decreased the replication rate of the PI-resistant strain, while ins35G had a protective effect.
Keywords: HIV-1; Protease; Insertion; Drug resistance; Viral replication