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Journal of Virology, October 2006, p. 9347-9348, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.01703-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Proteolytic cleavage of the influenza virus hemagglutinin (HA) is essential for virus replication, but the relevant human proteases have not been defined. During a search for such proteases, Böttcher et al. (p. 9896-9898) cloned two trypsinlike proteases, TMPRSS2 and HAT, from human airway epithelial cells. Either protease can cleave HA and support virus infection in vitro in the absence of trypsin. This work establishes a new approach for the identification of proteases involved in influenza virus replication and pathogenicity in humans.

Human Polyomavirus JC Exploits Novel Intracellular Sorting Pathway To Infect Cells

Invasion of host cells by the polyomavirus JC (JCV) is a multistep process that begins with initial attachment to sialic acid receptors. The virus subsequently binds to the 5HT2a receptor to facilitate entry by clathrin-dependent endocytosis. Querbes et al. (p. 9402-9413) now show that JCV associates with caveolin-1-containing membrane microdomains on early endosomes and is sorted to caveosomes in a pH-dependent mechanism. This work identifies a novel role for caveolae in endosomal sorting of ligands entering cells by clathrin-dependent uptake.

Test Tube Herpesvirus Leaving Its Nuclear Birthplace

Herpesviruses replicate and assemble their new capsids in the nucleus and reach the cell surface by a poorly characterized process. Rémillard-Labrosse et al (p. 9741-9753) have studied this pathway by reconstituting herpes simplex virus type 1 (HSV-1) nuclear egress in vitro. They unambiguously show that naked capsids are released into the cytosol by direct passage across the two nuclear membranes. This process is time, temperature, and energy dependent. Oddly, host cytosolic proteins are also required. This assay has the potential to elucidate the molecular details of HSV-1 egress.

Poliovirus Attenuation through Codon Deoptimization

Synonymous codon optimization by de novo gene synthesis is becoming increasingly popular to improve cross-species protein expression. Mueller et al. (p. 9687-9696) have generated attenuated polioviruses by intentional introduction of suboptimal synonymous codons to diminish protein synthesis. This work suggests that reduction of the rate of genome translation leads to an increased rate of abortive infection and lower specific infectivity of the viral particle. Codon deoptimization may have broad applicability in vaccine development.

Lethality of West Nile Virus Infection Correlates with Viral Control of Type I Interferon Signaling

West Nile virus (WNV) can inhibit signaling by alpha/beta interferons (IFN), yet the exact benefits of this property are not known. Keller et al. (p. 9424-9434) show that pathogenic WNV blocks STAT1/2 phosphorylation, whereas a strain with a weakened capacity to antagonize IFN signaling is attenuated. Strikingly, infection of mice lacking a functional IFN system with the nonpathogenic WNV strain results in lethality. This work underscores the importance of IFN in controlling WNV virulence and identifies a key functional difference between epidemic and nonpathogenic WNV strains.

Pathogenic Hantaviruses Regulate the Interferon Signaling Pathway

Hantaviruses cause two types of acute vascular disease. However, it is unclear what differentiates pathogenic and nonpathogenic hantaviruses. Alff et al. (p. 9676-9686) show that the G1 cytoplasmic tail of pathogenic, but not nonpathogenic, hantaviruses regulates cell-signaling pathways that direct the induction of early beta interferon responses. The G1 tail blocks interferon induction upstream of activated IRF-3 and appears to function at the level of the TBK-1 signaling complex. These findings suggest that the G1 cytoplasmic tail contains a virulence element that determines the capacity of hantaviruses to bypass innate cellular immune responses and successfully replicate within human endothelial cells.

Cytotoxic T Lymphocytes Are a Dominant Selective Force in Human Immunodeficiency Virus Type 1 Infection

Selective forces driving human immunodeficiency virus type 1 (HIV-1) evolution over the course of infection are poorly understood. Liu et al. (p. 9519-9529) conducted an intensive 3-year longitudinal study in one subject, beginning in acute infection. They showed that the majority of amino acids undergoing selection are within cytotoxic T-lymphocyte (CTL) epitopes, leading to viral escape or to potential reversion of CTL epitope sites recognized by the immune system of the transmitting partner. This work confirms CTL as a dominant selective force in HIV-1 infection.

Characterizing Human Immunodeficiency Virus-Specific T-Cell Responses in Vaccinees Who Acquire HIV Type 1 Infection

The effect of immunization with T-cell-based human immunodeficiency virus (HIV) vaccines entering efficacy trials on postinfection T-cell immunity is unknown. Horton et al. (p. 9779-9788) examined T-cell responses in persons who became infected while participating in canarypox HIV vaccine trials. They show that the capacity of a vaccinee to elicit an HIV-specific T-cell response postinfection is not compromised by previous immunization. They also describe a novel HIV-specific CD8⁺ T-cell response in an individual exhibiting extraordinary control of infection. This work highlights the importance of comprehensive studies of breakthrough infections in vaccine trials to identify immunologic features responsible for controlling viral replication.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content