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SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies of B lymphocytes and epithelial cells. Like other herpesviruses, EBV uses three glycoproteins, gB, gH, and gL, to mediate membrane fusion. For infection of B cells, EBV additionally requires gp42, which forms a complex with gH/gL. Kirschner et al. (p. 9216-9229) identify key gp42 residues for gH/gL binding and demonstrate that a peptide containing these residues is a potent (nanomolar) inhibitor of membrane fusion. The gp42 peptide also inhibits EBV infection of epithelial cells, providing a lead antiviral entry inhibitor with therapeutic potential.

Mn²⁺ Blocks Reverse Transcription via an Effect on RNAse H

Reverse transcription by the yeast retrotransposon, Ty1, is blocked in cells expressing mutant forms of pmr1 via a process involving elevated intracellular Mn²⁺ concentrations. However, the underlying biochemical mechanism remained unknown. Yarrington et al. (p. 9004-9012) isolated pmr1 suppressor mutants of Ty1 that were capable of reverse transcription despite high Mn²⁺ concentrations. Surprisingly, these mutations mapped to the RNAse H domain rather than the polymerase domain of Ty1 pol. The Mn²⁺-resistant reverse transcriptase activity in these mutants suggests that the mutant RNAse H domains biochemically communicate with the polymerase domain to allow tolerance of elevated Mn²⁺.

Staying in Control: Manipulating Cellular Protein Function by Poliovirus

The cellular RNA-binding protein, poly(rC)-binding protein 2 (PCBP2), is required for both translation and replication of poliovirus genomic RNA. These intracellular processes proceed in opposing directions and cannot occur simultaneously on the same template RNA. Perera et al. (p. 8919-8932) demonstrate that poliovirus effectively shifts from viral translation to replication of its RNA by using a viral proteinase to cleave PCBP2, thereby producing a novel protein with a specific function in RNA replication. This work provides new insights into an intriguing mechanism utilized by poliovirus that involves modification of PCBP2 to control template selection.

A New E6/P63 Pathway Modulates the Transcriptome in Cervical Cancer

Expression of human papillomavirus E2 in HeLa cells activates a cluster of p53 target genes and represses a group of mitotic E2F target genes through transcriptional repression of the viral E6 and E7 oncogenes. Teissier et al. (p. 9368-9376) now identify a novel p63 pathway among the E2-activated genes. An approach that relies on small interfering RNA demonstrates that the p63 target genes are activated by silencing of the E6/E6AP pathway. These results identify new biomarkers of the evolution of cervical cancer.

NS1 Antibodies Target West Nile Virus-Infected Cells for Host Clearance

Flavivirus NS1 is a secreted glycoprotein that accumulates in serum and becomes associated with the surface of infected cells. A subset of monoclonal antibodies against NS1 protect against lethal infection even though this protein is absent from the virion. Using mice and cells with deficiencies of specific Fc- receptors, Chung et al. (p. 9551-9555) show that anti-NS1 antibodies that recognize cell surface-associated NS1 trigger Fc- receptor I- or IV-mediated phagocytosis by macrophages and clearance of West Nile virus-infected cells. These findings may be relevant for targeting novel therapeutic antibodies or flavivirus vaccines against the NS1 protein.

Baculovirus Apoptosis Inhibitors Target Required Caspases in Drosophila melanogaster

Mechanisms by which viruses trigger apoptosis are poorly understood. Lannan et al. (p. 9319-9330) describe a useful Drosophila system to define host apoptotic signals. The authors demonstrate that the principal effector caspase, DrICE, is required for baculovirus-induced apoptosis. Surprisingly, baculovirus apoptosis suppressor P49 inhibited this effector caspase, but not an initiator caspase, which is targeted by P49 in other insects. Thus, baculoviruses exhibit greater versatility for inactivating host caspases than previously thought.

Anti-Gal-Mediated Targeting of Influenza Virus Vaccine to Antigen-Presenting Cells

Vaccine efficacy depends on effective antigen uptake by antigen-presenting cells (APCs) at the vaccination site. Viral vaccines can be targeted for uptake by APCs after in situ formation of immune complexes with natural anti-Gal antibody. Anti-Gal constitutes 1% of immunoglobulins in humans and binds to -gal epitopes. Abdel-Motal et al. (p. 9131-9141) demonstrate, using a mouse model, increased T- and B-lymphocyte responses to influenza virus vaccines engineered to express -gal epitopes and increased protection against influenza virus challenge. These findings suggest that expression of -gal epitopes on influenza virus vaccines will enhance their immunogenicity.

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