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Journal of Virology, August 2007, p. 8373, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.01325-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

The Japanese encephalitis virus (JEV) capsid protein is generated from a precursor polyprotein by processing with host and viral proteases. Mori et al. (p. 8477-8487) show that further processing of the capsid protein by cathepsin L is involved in the replication of JEV in neural and macrophage cell lines. This work suggests that JEV uses a novel mechanism to infect host cells via cathepsin-mediated processing of the capsid protein.

Nodavirus RNA Polymerase Synthesis Requires Cellular Chaperones

Genome translation is an essential early step in the life cycle of positive-sense RNA viruses and often involves manipulation of the cellular translation apparatus to benefit the invading virus. Castorena et al. (p. 8412-8420) demonstrate that heat shock protein 90, an abundant cellular chaperone implicated in the replication of numerous viruses, facilitates the efficient synthesis of Flock House virus RNA polymerase. This work highlights the diverse mechanisms whereby viruses exploit cellular machinery to accomplish specific tasks to achieve their replication.

Rotavirus-Induced Alteration of Occludin Expression

Rotavirus can affect the intestinal barrier by diminishing the integrity of tight junctions (TJs). Beau et al. (p. 8579-8586) demonstrate that rhesus monkey rotavirus (RRV) alters the expression of occludin, an integral TJ protein, in enterocyte-like Caco-2 cells. The disappearance of occludin from the TJ plane, decrease in the nonphosphorylated form of occludin, and diminished levels of occludin mRNA are antagonized by inhibitors of protein kinase A (PKA). This work suggests that rotavirus uses PKA-dependent mechanisms to alter TJ function, which might in turn contribute to its pathogenicity or dissemination.

Human Immunodeficiency Virus Escape from Potent Neutralizing Antibodies

A recent clinical trial evaluated neutralizing monoclonal antibodies (MAbs) 2F5 and 4E10 targeting the membrane-proximal external region (MPER) of human immunodeficiency virus (HIV) gp41 together with the carbohydrate-specific MAb 2G12. The results demonstrated that once resistance to 2G12 had evolved, viral replication resumed despite MPER antibody treatment without evidence of escape mutations to these MAbs. Manrique et al. (p. 8793-8808), using cell-culture-based systems, now show that resistance to the MPER MAbs is difficult to achieve and can lead to selection of variants with impaired infectivity. This vulnerability of the virus to interference with the MPER supports the importance of this target in vaccine design.

Superior Smallpox Vaccine Candidates with Integrated Interleukin-15

A smallpox vaccine suitable for contemporary populations with greater numbers of immunodeficient individuals is a priority. Perera et al. (p. 8774-8783) report that the integration of the pleotropic cytokine interleukin-15 (IL-15), which is essential for both innate and adaptive immune responses, into the genome of either a Wyeth vaccine strain derived from the Dryvax vaccine or a nonreplicative modified vaccinia virus Ankara strain results in vaccine candidates with superior immunogenicity, durable efficacy, and safety. These IL-15-integrated derivatives hold promise as more efficacious and safe alternatives to the Dryvax vaccine.

Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins Are Functional and Immunogenic

The extensive diversity found in human immunodeficiency virus type 1 (HIV-1) vexingly challenges vaccine development. Rolland et al. (p. 8507-8514) developed a phylogenetics-informed algorithm to reconstruct ancestral HIV-1 sequences, called center-of-tree (COT). COT sequences are designed to minimize genetic distances between the antigen and circulating isolates. Computationally derived COT proteins corresponding to HIV-1 subtype B Gag, Tat, and Nef were generated and shown to retain the functionality of the extant proteins and elicited antigen-specific cellular immune responses in mice. This work establishes a new tool for rational vaccine design.

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