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SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Poliovirus RNA replication complexes are associated with membranous vesicles formed by virus-induced remodeling of subcellular organelle structures. Arf GTPases, which regulate specific steps of membrane trafficking in the protein secretory pathway, accumulate on viral replication complexes in infected cells. Belov et al. (p. 558-567) now identify three Arf GEFs (guanine nucleotide exchange factors) that activate Arf and are recruited to membranes by two different viral proteins, 3A and 3CD. The involvement of these GEFs explains the sensitivity of virus growth to brefeldin A and implicates a new set of virus-host cell protein interactions in viral RNA synthesis.

Adenovirus Ubiquitin-Protein Ligase Stimulates Late mRNA Nuclear Export

The adenovirus type 5 (Ad5) E1B-55K and E4orf6 proteins, long known to inhibit p53 and stimulate viral late mRNA nuclear export, were recently discovered to associate with cellular proteins to form a viral ubiquitin-protein ligase that polyubiquitinates p53 and probably the cellular MRE11-RAD50-NBS1 DNA double-strand break repair complex. Woo and Berk (p. 575-587) now provide strong evidence that the activity of this adenovirus ubiquitin-protein ligase is also required for efficient nuclear export of viral late mRNAs. This finding suggests that virus-directed proteasomal degradation of a cellular protein prevents an antiviral response that would otherwise inhibit viral mRNA nuclear export.

Pseudotyped Lentiviral Vector Preparations Carry DNA and Stimulate Antiviral Responses via Toll-Like Receptor 9

Innate antiviral responses elicited by lentiviral vectors can curtail their use in therapy and research. Pichlmair et al. (p. 539-547) now show that some of these responses are not elicited by virus particles but by by-products of lentivirus production. Transient transfection with vesicular stomatitis virus G protein (VSV-G)-encoding plasmids used in production of VSV-G-pseudotyped lentiviral vectors leads to accumulation in cell supernatants of tubulovesicular structures that cofractionate with virions and carry plasmid DNA used in transfection. The DNA acts as a stimulus for TLR9, an innate receptor that can trigger type I interferon production by specialized plasmacytoid dendritic cells. Purification of lentiviral vectors to exclude tubulovesicular structures may help render them immunologically silent.

Exposing Interferon-Stimulated Gene Expression in the Virus-Infected Brain

The interferon-stimulated genes (ISG)-49, -54 and -56 encode a family of proteins that are highly inducible by type I interferons (IFN) but whose expression and functions in vivo are ill-defined. Wacher et al. (p. 860-871) now show that expression of these ISGs is markedly upregulated early and in a differential pattern in the brain during infection with two distinct viruses, lymphocytic choriomeningitis virus and West Nile virus. The characterization of the expression and function of these ISGs in response to infection in the host is an important step toward a better understanding of the virus-host interactions that influence the outcome of infection.

Complement Components Modulate Enhanced Respiratory Syncytial Virus Disease

In 1966, a formalin-inactivated vaccine against respiratory syncytial virus (RSV) was administered to infants and young children in the United States. Immunized children developed enhanced pulmonary disease (EPD) when exposed to RSV in the community. Melendi et al. (p. 991-999) describe a negative modulatory function for complement factor C5 on EPD severity and a critical role for C3a in bronchoconstriction. The negative effect of C5 is mediated by modulation of C3a expression in pulmonary epithelium.

Mechanisms of Gastrointestinal CD4⁺ T-Cell Loss Induced by Human Immunodeficiency Virus Type 1

A significant loss of gastrointestinal (GI) CD4⁺ T cells occurs during acute and early human immunodeficiency virus type 1 (HIV-1) infection (AEI). Mehandru et al. (p. 599-612) report that during AEI, the GI tract harbors a significantly greater number of HIV-1-infected CD4⁺ T cells than does peripheral blood. Mucosal CD4+ T-cell infection is associated with high levels of immunological activation and a robust cytotoxic response. This study provides evidence that mucosal CD4⁺ T-cell loss is multifactorial and extends an understanding of early events in HIV-1 pathogenesis.

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