Journal of Virology, June 2005, p. 7281-7282, Vol. 79, No. 12
0022-538X/05/$08.00+0 doi:10.1128/JVI.79.12.7281-7282.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
| SPOTLIGHT |
Articles of Significant Interest Selected from This Issue by the Editors
Insight into the Cell Entry Mechanism of a Nonenveloped VirusThe interaction of poliovirus, a nonenveloped virus, with its receptor triggers a conformational change in which internal peptides become exposed, interact with cellular membranes, and permit the virus or its RNA genome to penetrate cells and initiate infection. Bubeck et al. (p. 7745-7755) have used cryoelectron microscopy to determine the structure of this cell-entry intermediate, the 135S particle, as a step toward understanding the molecular mechanism of membrane penetration. This work visualizes a key polypeptide on the outer surface of the virus and reveals the shift of neighboring proteins that makes peptide externalization possible.
Adenovirus Infects Liver Cells by Binding to Blood Factors
Commonly used human adenovirus (Ad) serotype 5-based gene transfer vectors require the coxsackievirus and adenovirus receptor (CAR) for efficient infection of cultured cells. However, after intravascular inoculation, liver cells are infected in a CAR-independent manner by an unknown mechanism. Gaggar et al. (p. 7503-7513) show that blood coagulation factor IX and complement component C4 binding protein can mediate CAR-independent infection of liver cells. This work has implications for the development of safer and more efficient Ad vectors for gene delivery.
Interferon Antagonist of Rabies Virus Identified
Viral interferon antagonists are key virulence factors. Brzózka et al. (p. 7673-7681) present new evidence that the phosphoprotein (P) of rabies virus interferes with transcriptional activation of the beta interferon (IFN) gene by inhibiting phosphorylation of interferon regulatory factor 3. The capacity of P protein to act as an IFN antagonist is new to this virus family. Although P is an essential and multifunctional virus protein, it was possible to engineer replication-competent P-mutant rabies viruses that induce IFN. This work may provide the basis for novel therapeutics and live vaccines.
Nodamuravirus Protein B2 Inhibits Mammalian RNA Interference
Nodamuravirus (NoV) is unique among the nodaviruses in that it infects mammalian and insect hosts. In insects, infection with some nodaviruses triggers an RNA interference (RNAi) response, which is inhibited by the viral protein B2. Sullivan and Ganem (p. 7371-7379) now show that NoV B2 also functions as an RNAi inhibitor in mammalian cells. They demonstrate that unlike other inhibitors, NoV B2 binds to multiple RNA intermediates of the RNAi pathway, providing a likely mechanism of inhibition. These results shed light on viral interactions with the insect and mammalian RNAi machinery.
Interferon Regulatory Factor Gene Expression Exposed in the Brain
Interferon regulatory factors (IRFs) are a family of transcription factors that regulate the expression of interferon (IFN) and other genes during viral infection. Little is known about the regulation of these genes in vivo. Ousman et al. (p. 7514-7527) show that expression of the IRF-7 and IRF-9 genes is markedly increased in a variety of cells, including neurons, following infection of the brain with lymphocytic choriomeningitis virus. A major difference in the regulation of these genes was identified, with IRF-7 but not IRF-9 gene expression being stimulated in a STAT1-independent fashion. Thus, IRF-7 and IRF-9 are dynamically and differentially regulated in the brain during viral infection.
Different Molecular Targets Are Required for Tumor Progression in Different Cell Types
Expression of SV40 T antigen induces tumorigenesis in numerous systems by interfering with cellular proteins such as the p53 and retinoblastoma tumor suppressors. p53 is mutated in 70% of all cancers, demonstrating its central importance in tumorigenesis. Markovics et al. (p. 7492-7502) now show that T antigen disruption of p53 does not play a role in the progression from hyperplasia to dysplasia in the small intestine. This work highlights tissue-specific differences and their diverse responses to oncogenic stimuli.
Dissecting Human Cytomegalovirus Immediate-Early Protein Functions
Human cytomegalovirus (HCMV) encodes two major immediate-early proteins with identical N termini. White and Spector (p. 7438-7452) used a recombinant virus with a deletion in the shared region to differentiate functions provided by the dispensable IE1 72-kDa protein versus the essential IE2 86-kDa protein. They show that the IE1 and IE2 proteins contribute independently to virus production and to the altered expression of cellular proteins during the progression of infection. This work further elucidates early events in HCMV infection that are required for efficient virus replication.
EBV Latent Membrane Protein 2A Enhances BCR Signaling in a Transgenic Mouse Model
Previous studies using Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines demonstrated that LMP2A inhibits B-cell receptor (BCR) signaling. Swanson-Mungerson et al. (p. 7355-7362) use a transgenic mouse model to provide new evidence that LMP2A does not block BCR signaling in primary murine B cells. In contrast, LMP2A actually enhances signals induced through the BCR. Furthermore, LMP2A-expressing B cells exhibit constitutive activation of NF-
B, showing that LMP2A may positively regulate this transcription factor. Overall, these findings suggest that LMP2A does not inhibit BCR-induced signals under all conditions as previously suggested from studies using EBV-immortalized B cells.
Peptide Antagonists Inhibit Cell Entry of Sin Nombre and Hantaan Virus
Specific therapy is not available for treatment of the life-threatening hantavirus cardiopulmonary syndrome (HCPS) caused by Sin Nombre virus (SNV) or Hantaan virus (HTNV). Entry of these pathogenic hantaviruses is dependent on expression of ß3 integrin at the cell surface, a process blocked by anti-integrin antibodies. Larson et al. (p. 7319-7326) use a novel approach based on phage display to identify cyclic peptides that interfere with interactions of integrin antibody and ß3. Furthermore, a subset of these peptides were found to substantially inhibit entry of pathogenic hantaviruses into otherwise susceptible cells. These peptides can be used in in vivo studies and as lead compounds for further structural optimization and consequent enhancement of activity.
MVA Smallpox Vaccine Is Safe and Protects against Lethal Respiratory Challenge with Monkeypox Virus
Smallpox virus is considered a significant bioterrorism threat. Classical smallpox vaccines are associated with rare but severe side effects. Stittelaar et al. (p. 7845-7851) show that a third-generation smallpox vaccine, modified vaccinia Ankara (MVA), is not only safe, but protects macaques from lethal infection with monkeypox virus, a virus closely related to smallpox virus, when administered by the natural respiratory route. This work indicates that MVA is an important candidate for protection of humans against smallpox.
Journal of Virology, June 2005, p. 7281-7282, Vol. 79, No. 12
0022-538X/05/$08.00+0 doi:10.1128/JVI.79.12.7281-7282.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
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