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Journal of Virology, December 2005, p. 15005-15006, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15005-15006.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Rotavirus subviral particles (SVPs) direct viral transcription and are morphogenic precursors of mature virions. The maturation of SVPs is mediated by NSP4, a resident glycoprotein of the endoplasmic reticulum. Silvestri et al. (p. 15165-15174) have found, by using RNA interference, that depletion of NSP4 leads to numerous changes within the infected cell, including marked increases in positive-strand RNA synthesis. This work indicates that one of the important functions of NSP4 is to act as a feedback inhibitor of transcription when positive-strand RNA levels become adequate for productive infection.

SARS Coronavirus Papain-Like Protease Is a Deubiquitinating Enzyme

Bioinformatic analysis suggests that the SARS coronavirus papain-like protease (SARS CoV PLpro) has structural and functional similarity to a cellular deubiquitinating enzyme. Barretto et al. (p. 15189-15198) and Lindner et al. (p. 15199-15208) provide independent experimental evidence demonstrating that the core domain of SARS CoV PLpro mediates deubiquitinating activity. These results have important implications for antiviral drug development and open new avenues for investigating novel strategies that the virus may use to modulate the host cell ubiquitination machinery.

A Ubiquitin-Specific Protease Activity in Herpesviruses

Herpes simplex virus type 1 (HSV-1) expresses a ubiquitin-specific protease activity embedded in UL36, the largest HSV-1 open reading frame, which encodes a tegument protein. This activity, released as the N-terminal segment of UL36 and unrelated to any of the known host ubiquitin-specific proteases, may well be conserved across the Herpesviridae, a prediction now confirmed by Schlieker et al. (p. 15582-15585). This activity may thus be important for herpesviruses more generally, which raises the possibility of generating small molecule inhibitors of this protease as antiviral agents.

Regulation of Hepatitis C Virus NS3 Helicase by Protein Phosphatase 2Ac

Hepatitis C virus (HCV) nonstructural protein 3 (NS3) has serine protease and NTPase/RNA helicase activity. NS3 can be methylated on an arginine residue in the helicase domain by protein arginine methyltransferase 1 (PRMT1), but the role of this modification is unknown. Duong et al. (p. 15342-15350) now show that arginine methylation of the NS3 helicase inhibits its enzymatic activity. Interestingly, this work further suggests that HCV can protect its helicase domain from becoming methylated by the upregulation of protein phosphatase 2A, a protein that can bind and inhibit PRMT1.

SARS Coronavirus Replication in Ciliated Airway Epithelial Cells

The identification of several coronaviruses that cause severe human respiratory disease demonstrates the need for relevant models systems to study mechanisms of pathogenesis and virulence in the human lung. Sims et. al. (p. 15511-15524) developed the first SARS-CoV indicator virus expressing GFP and demonstrated ACE2-dependent entry, replication, and spread of SARS-CoV within ciliated cells of an in vitro model of the human airway epithelium that recapitulates the morphological and physiological features of the human airway epithelium in vivo. This model provides an opportunity to investigate the unique physiological and innate defense functions of ciliated airway epithelial cells in the human lung following human coronavirus infection.

SOCS Proteins Are Involved in Hepatitis C Virus Core/gC1qR-Mediated T-Cell Suppression

In this report, Yao et al. (p. 15417-15429) demonstrate that hepatitis C virus (HCV) core proteins from chronic and recovered patients exhibit different sequences, gC1qR-binding capacity, and T-cell inhibitory effects. This core/gC1qR-induced suppression of T-cell proliferation and gamma interferon production is mediated by disruption of Jak/STAT activation through the induction of SOCS1 as well as SOCS3 proteins, a new family of inhibitors of cytokine signaling. This finding represents a novel mechanism by which a virus usurps host machinery to establish persistence.

Bottlenecking during Sexual Transmission Prevents Hepatitis C Virus Persistence

Sexual partners of hepatitis C virus (HCV) carriers often have HCV-specific T-cell responses suggesting innaparent resolved infection. Quer et al. (p. 15131-15141) compared multiple NS3 sequences from a chronic carrier with those of a sexual partner with acute resolving infection. All acute-phase sequences were found to cluster within a single sequence from the infecting carrier, despite a complete HLA mismatch between the patients. These findings suggest that transmission of a limited number of viral particles impairs the potential of the quasispecies to diversify and overcome the adaptive immune response of the exposed host. Furthermore, these results may explain the low risk of HCV persistence after sexual exposure.

Novel Mechanism of Biphasic Regulation of Interleukin-8 by Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV), a major cause of pediatric airway disease, first stimulates but later attenuates IL-8 expression. Jamaluddin et al. (p. 15302-15313) find that this late-phase inhibition is mediated by the IB-like Bcl3 protein. Expressed in response to RSV infection, Bcl-3 enters the nucleus to inhibit the action of the NF-B and STAT transcription factors. Interestingly, Bcl-3 association does not interfere with DNA binding but, instead, recruits the repressor molecule, histone deacetylase 1, to the IL-8 promoter. This finding sheds new light on the epithelial cell response to RSV by sequential activation and subsequent inhibition of immune response genes.

Escape Is Futile

A number of HIV vaccination strategies employing adenovirus (Ad) vectors with HIV transgene inserts will enter clinical trials in the next 5 years. Ad vectors elicit robust and durable cellular immune responses, which are thought to be required for the control of HIV infection. However, virus escape mutations can render vaccine-induced immune responses ineffective, leading to loss of virus control, increased virus burden, and disease progression. McDermott et al. (p. 15556-15566) vaccinated rhesus macaques with DNA-Gag followed by Ad5-Gag. Although the animals mounted strong CD8⁺ T-cell responses against known immunodominant epitopes, these responses did not invariably select escape mutations leading to vaccine failure.

Genetics and Chance in Host Immunity and HIV-1 Evolution

The determinants of cellular immune targeting and how it influences HIV-1 sequence evolution are poorly understood. Yang et al. (p. 15368-15375) address the roles of genetics versus chance in a detailed study of identical twins infected with one strain of HIV-1. Cytotoxic T-lymphocyte viral targeting was found to be similar and therefore largely genetically determined. However, the random process of T-cell receptor generation yields distinct T-cell receptors between twins, likely resulting in divergent HIV-1 sequence evolution. These data illustrate unpredictability in the virus-host interaction, which may have implications for vaccine design.

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