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Antiviral Research (v.70, #2)
Treatment of respiratory virus infections by Yacine Abed; Guy Boivin (pp. 1-16).
Respiratory viral infections (RVIs) can be associated with a wide range of clinical manifestations ranging from self-limited upper respiratory tract infections to more devastating conditions, such as pneumonia. RVIs constitute the most frequent reason for medical consultations in the world and they have a considerable impact on quality of life and productivity. Therefore, the prevention and control of RVIs remain major clinical goals. Currently, there are approximately 200 known respiratory viruses that can be grouped into one family of DNA viruses ( Adenoviridae) and four families of RNA viruses ( Orthomyxoviridae, Paramyxoviridae, Picornaviridae and Coronaviridae). In this paper, we review the major respiratory viruses that cause disesases in humans, with an emphasis on current treatment options.
Keywords: Viral infections; Epidemic influenza; Respiratory viruses; Antivirals
Antiviral activity and cross-resistance profile of P-1946, a novel human immunodeficiency virus type 1 protease inhibitor by G. Sévigny; B. Stranix; B. Tian; A. Dubois; G. Sauvé; C. Petropoulos; Y. Lie; N. Hellmann; B. Conway; J. Yelle (pp. 17-20).
The HIV protease inhibitor P-1946 is a member of a novel family ofl-Lysine derivatives. The compound is a specific HIV-1 protease inhibitor that has potent and selective in vitro antiviral activity (EC50 152nM) against a range of isolates resistant to commercially available protease inhibitors. The presence of at least four primary and four secondary drug resistance mutations is required to achieve greater than four-fold resistance to P-1946. P-1946's favorable resistance profile makes it a good lead for the development of new agents active against existing PI-resistant virus in treatment-experienced patient.
Keywords: Protease inhibitors; P-1946; HIV-1 resistance
Detection of very early antibody to native HIV antigens by HIV neutralization and live-cell immunofluorescence assays by Jingzhi Pan; Jianmin Chen; Hung Lee; Gautam K. Sahu; Joyce S. Poast; Stephen Tyring; Miles Cloyd; Samuel Baron (pp. 21-27).
Very early detection of HIV infection could help decrease the spread of HIV, improve safety of the blood supply, and permit earlier treatment. Early detection was reported when native gp41 antigen was used to detect antibodies that occurred 2–6 weeks earlier than detection of antibodies to denatured antigens by the current EIA or WB tests or detection by the HIV RNA test. We hypothesized that early antibodies to native gp41/160 could be detected, not only by the reported live-cell immunofluorescence (IFA) but also by a neutralization test, since virions as well as HIV-infected cells contain native gp41/160. To test this hypothesis, we did an initial test of concept study to compare the neutralization test with other tests, using sera from 12 high-risk patients. The neutralization test reproducibly detected early antibodies (characterized) in the sera of 10 of 12 (83%) high-risk subjects. Importantly, the EIA and WB tests that use denatured antigens missed the early diagnosis in 12 of the 13 subjects (92%). The findings support the concept that native HIV antigens can detect polyclonal HIV neutralizing antibodies and live-cell IFA antibodies earlier than currently available tests that use denatured antigens.
Keywords: HIV; Early diagnosis; Antibody; Native antigens; Neutralization test
Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034 by Xiao Tong; Robert Chase; Angela Skelton; Tong Chen; Jackie Wright-Minogue; Bruce A. Malcolm (pp. 28-38).
HCV NS3 protease variants resistant to the protease inhibitor SCH 503034 were selected. Three mutations, T54A, V170A and A156S mutations conferred low to moderate levels of resistance (<20-fold). Longer exposure (>10 passages) or selection with higher levels of compound led to the selection of a more resistant variant, A156T (>100-fold). [Lin, C., Lin, K., Luong, Y.P., Rao, B.G., Wei, Y.Y., Brennan, D.L., Fulghum, J.R., Hsiao, H.M., Ma, S., Maxwell, J.P., Cottrell, K.M., Perni, R.B., Gates, C.A., Kwong, A.D., 2004. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol. Chem. 279(17), 17508–17514; Lu, L., Pilot-Matias, T.J., Stewart, K.D., Randolph, J.T., Pithawalla, R., He, W., Huang, P.P., Klein, L.L., Mo, H., Molla, A., 2004. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob. Agents Chemother. 48(6), 2260–2266.] Combination with IFN-α drastically reduced the number of emergent colonies. Resistant colonies showed no change in sensitivity to IFN-α.Although the A156T mutation conferred the highest level of resistance to SCH 503034, it significantly reduced the colony formation efficiency (CFE) of the mutant replicon RNA, and rendered replicon cells less fit than those bearing wild-type replicons. Replicon cells bearing mutation A156S were less fit than wild-type in co-culture growth competition assays but showed no impact on CFE. The V170A mutation, on the other hand, did not affect replicon fitness in either assay, which was consistent with its emergence as the dominant mutant after 12 months of continuous selection. The reduced fitness of the most resistant variant suggests that it may be rare in naïve patients and that development of high-level resistance may be slow. Combination therapy with IFN-α should also greatly reduce the potential emergence of resistance.
Keywords: Hepatitis C virus; Protease; Inhibitor; Resistance; Antiviral
Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen by Baohua Gu; Serguey Ouzunov; Liguan Wang; Peter Mason; Nigel Bourne; Andy Cuconati; Timothy M. Block (pp. 39-50).
West Nile virus (WNV) is a positive-sense, single-stranded RNA virus of the family Flaviviridae. WNV persistently infects insect cells, but can causes acute cytopathic infection of mammalian cells and is an etiologic agent of viral encephalitis in humans. By using a cell line expressing a WNV subgenomic replicon [Rossi, S.L., Zhao, Q., O’Donnell, V.K., Mason, P.W., 2005. Adaptation of West Nile virus replicons to cells in culture and use of replicon-bearing cells to probe antiviral action. Virology 331 (2), 457–470], we developed a high-throughput assay and used it to screen a library of small molecule compounds for inhibitors of WNV replication in the absence of live virus. Here we report the identification of novel small molecule inhibitors for WNV replicon replication. We demonstrate that the compounds inhibited WNV replication-dependent luciferase expression in the replicon cells and reduced WNV viral protein accumulation and viral RNA copy number in the replicon cells. Two classes of compounds with multiple hits, parazolotrahydrothophenes and pyrozolopyrimidines, showed preliminary structure–activity relationships. In WNV infection assays, one pyrozolopyrimidine compound was confirmed to have antiviral activity. These compounds should be valuable for developing anti-WNV therapeutic drugs as well as research tools to study the mechanism of WNV replication.
Keywords: High-throughput screen (HTS); West Nile virus; Small molecule inhibitor
Cooperative contribution of gag substitutions to nelfinavir-dependent enhancement of precursor cleavage and replication of human immunodeficiency virus type-1 by Saori Matsuoka-Aizawa; Hiroyuki Gatanaga; Hironori Sato; Kazuhiko Koike; Satoshi Kimura; Shinichi Oka (pp. 51-59).
We previously described a clinical human immunodeficiency virus type-1 (HIV-1) isolate, CL-4, which showed nelfinavir (NFV)-dependent enhancement of replication (Matsuoka-Aizawa, S., Sato, H., Hachiya, A., Tsuchiya, K., Takebe, Y., Gatanaga, H., Kimura, S., Oka, S, 2003. Isolation and molecular characterization of a nelfinavir (NFV)-resistant human immunodeficiency virus type 1 that exhibits NFV-dependent enhancement of replication. J. Virol. 77, 318–327.). To identify the responsible region(s) of HIV-1 proteins for such replication enhancement, we constructed a panel of recombinant HIV-1 clones harboring portions of the Gag and protease of CL-4 and analyzed their replication capabilities and Gag processing patterns. Our data suggested that the substitutions in the matrix and N-terminal half of capsid of CL-4 were indispensable for the NFV-dependent enhancement of replication and that NFV facilitated the cleavage between the matrix and capsid of the Gag precursor harboring these substitutions. The substitutions in C-terminal half of capsid rather decreased the cleavability of Gag precursor and NFV counteracted such negative impact. Efficient replication enhancement with NFV can be observed only in the presence of the substitutions in entire Gag and protease of CL-4.
Keywords: Human immunodeficiency virus type 1; Nelfinavir-resistant; Gag mutation
Evaluation of synthetic oligonucleotides as inhibitors of West Nile virus replication by Paul F. Torrence; Nidhi Gupta; Carol Whitney; John D. Morrey (pp. 60-65).
A series of synthetic oligonucleotide phosphorothioate 15-mers were generated against specific sequences in the West Nile virus RNA genome. These antisense oligonucleotides targeted (1) conserved features of the West Nile virus RNA genome that may be expected to lead to inhibition of virus replication since such features play essential roles in the virus lifecycle; (2) G-quartet oligonucleotides with potential facilitated uptake properties and that also targeted conserved sequences among a range of West Nile virus strains. Several formulations with significant in vitro antiviral activity were found. Among the active oligonucleotides were examples that targeted both C-rich RNA sequences of the West Nile RNA genome as well as recognized conserved sequences key to West Nile virus replication. Since the antiviral activity of the latter oligonucleotides diminished upon 2′- O-methyl substitution, it is likely that their activity involves RNase H-catalyzed RNA degradation. One G-rich oligonucleotide that did not target a West Nile virus RNA sequence also was found. These results suggest the potential of antisense strategies for the control of West Nile virus replication if the attendant problem of oligonucleotide delivery can be adequately addressed.
Keywords: Conserved RNA sequences; G-quartet; Facilitated uptake; Ribonuclease H; 2′-; O; -Methyl-RNA oligonucleotides; Phosphorothioate
In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor by Akihiko Sato; Jennifer Hammond; Therese N. Alexander; Joanne P. Graham; Susan Binford; Ken-ichi Sugita; Hirohiko Sugimoto; Tamio Fujiwara; Amy K. Patick (pp. 66-74).
Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC50 values ranging from 0.7 to 10.3nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4–5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.
Keywords: Capravirine; Nonnucleoside reverse transcriptase inhibitor; HIV; Resistance
IL-12 deficiency transiently improves viral clearance during the late phase of respiratory tract infection with influenza A virus in mice by Koenraad F. van der Sluijs; Leontine J.R. van Elden; Yanling Xiao; Ramon Arens; Monique Nijhuis; Rob Schuurman; Sandrine Florquin; Henk M. Jansen; René Lutter; Tom van der Poll (pp. 75-84).
T helper 1-driven immune responses have been implicated in protective immunity against viral infections. Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a p35 and a p40 subunit that can induce differentiation of naïve T cells towards a T helper 1-response. To determine the role of IL-12 in respiratory tract infection with influenza, p35 gene deficient (p35−/−) and normal wild type mice were intranasally infected with influenza A virus. IL-12 p35−/− mice displayed a transiently enhanced rather than an impaired viral clearance, as indicated by a 10-fold reduction in viral loads on day 8 after infection. Although interferon-γ levels were significantly lower in the lungs of IL-12 p35−/− mice, their cellular immune responses were not altered, as reflected by similar T cell CD69 expression and influenza-specific T cell recruitment. Our data indicate that endogenous IL-12 impairs viral clearance during the late phase of influenza A virus infection in mice.
Keywords: Influenza; Pneumonia; Interleukin-12; Innate response
Identification of compounds that inhibit the interaction between core and surface protein of hepatitis B virus by M. Asif-Ullah; Kyoung-Jae Choi; Kyung-Il Choi; Yong-Joo Jeong; Yeon Gyu Yu (pp. 85-90).
Specific interactions of the human hepatitis B virus (HBV) surface proteins with the core protein of nucleocapsid are critical for the envelopment of virus particles, and inhibition of this process may prevent the production of infectious virus. A modified enzyme-linked immunosorbent assay (ELISA), which measured the interaction between the core protein and PreS region of the surface protein, was used to screen a chemical library for compounds that would block this interaction. Few inhibitory compounds were identified from a chemical library consisting of 5600 compounds. Among them, two compounds inhibited the production of HBV particles from transiently HBV-producing HuH7 cells. The IC50 values of these compounds for inhibition of HBV production in HuH7 cells were in the micromolar concentration range. These results indicate that compounds that prevent the interaction between the core protein and PreS region of the surface protein may possibly be useful as anti-HBV agents.
Keywords: HBV; HBs (surface) protein; HBc (core) protein; Anti-HBV compounds