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Journal of Virology, September 2008, p. 8245, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.01440-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Human coronavirus HKU1 (HCoV-HKU1) emerged in the wake of severe acute respiratory syndrome (SARS) and has achieved global distribution. HCoV-HKU1 is a group 2A coronavirus, distinct from group 2B coronaviruses such as the SARS coronavirus. It causes syndromes including the common cold, bronchitis, and pneumonia. Zhao et al. (p. 8647-8655) determined the crystal structure of the HCoV-HKU1 main protease, a key enzyme in viral replication and an attractive target for rational drug design. Combined with structural data for other coronavirus main proteases, this work provides insights into both substrate preference and the development of new coronavirus protease inhibitors.

Kaposi's Sarcoma-Associated Herpesvirus Drives Lymphatic Endothelial Cell Differentiation through gp130-Dependent Activation of Akt

Latent Kaposi's sarcoma-associated herpesvirus (KSHV) infection of blood endothelial cells causes differentiation to the lymphatic endothelium, the apparent cell type of Kaposi's sarcoma spindle cells. The developmental process of lymphatic endothelial cell differentiation is poorly understood. Morris et al. (p. 8771-8779) defined the signaling pathway required for virus-induced endothelial cell differentiation. KSHV stimulates cytokine receptor gp130, leading to the activation of Akt and STAT3 by Jak2 and the subsequent upregulation of Prox-1, a transcription factor required for blood-to-lymphatic endothelial cell differentiation. Thus, this pathway has relevance to both KSHV pathogenesis and lymphatic endothelial cell biology.

TLR3 Inhibition by a West Nile Virus Nonstructural Protein

Flavivirus NS1 protein is required for viral RNA replication and is secreted to high levels during infection. However, its overall function is not well understood. Wilson et al. (p. 8262-8271) show that the West Nile virus (WNV) NS1 protein inhibits TLR3-mediated signal transduction. Expression of NS1 blocks TLR3-mediated transcription and establishment of an antiviral state. This work identifies a novel role for the NS1 protein in inhibition of innate immune response signaling, which may influence WNV pathogenesis.

Bcl-2 Inhibitors Augment Vesicular Stomatitis Virus Oncolysis in Chronic Lymphocytic Leukemia

Nonpathogenic replicating RNA viruses, such as vesicular stomatitis virus (VSV), have emerged as potential cancer therapeutics because of their selective capacity to replicate in and kill tumor cells. However, a major obstacle to the implementation of this virotherapy is the resistance of many primary cancers to viral oncolysis. In leukemic malignancies, impaired apoptosis is correlated with disease progression. Tumilasci et al. (p. 8487-8499)now demonstrate that targeting the apoptotic pathway with a small-molecule Bcl-2 antagonist dramatically augments VSV-induced oncolysis in chronic lymphocytic leukemia. These results establish a rational approach to enhance the sensitivity of human leukemias to viral oncolysis.

Pathways of Cross-Species Transmission of Synthetically Reconstructed Zoonotic Severe Acute Respiratory Syndrome Coronavirus

Severe acute respiratory syndrome coronavirus (SARS-CoV) evolved from viruses circulating within wild animals in China, but the timing and mechanisms of emergence of the epidemic human strains remain unclear. Sheahan et al. (p. 8721-8732) used synthetic genomics, experimental evolution, and structure modeling to suggest that human epidemic strains likely evolved by repeated transfers between human and wild-animal hosts, thus providing the coevolutionary pressure to retain dual-species tropism. Retrospective serological analyses demonstrated that SARS-like viruses caused infections in humans as early as 2 years prior to the epidemic. Collectively, these data suggest that SARS-CoV cross-species transmission occurred multiple times prior to the epidemic of 2002 to 2003.

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