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Journal of Virology, October 2005, p. 12123-12124, Vol. 79, No. 19
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.19.12123-12124.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

Fusogenicity of the human immunodeficiency virus (HIV) envelope protein (Env) is limited by poorly defined interactions between the gp41 cytoplasmic tail (CT) and Gag proteins and is not fully enabled until Gag is cleaved by the viral protease. Wyss et al. (p. 12231-12241) show that even in the absence of Gag, HIV Env fusogenicity and kinetics are reduced by the CT, in particular by the LLP2 region, which likely interacts with cellular membranes. These findings suggest that during Env transport to sites of viral assembly and its subsequent incorporation into viral particles, the CT acts to restrain Env fusion function until the virion is formed and released from the cell.

Identification of the Bunyamwera Virus Transcription Promoter

Bunyamwera virus (BUNV) RNA replication requires nucleotides from both the 3' and 5' ends of the template. Barr et al. (p. 12602-12607) extend this work by showing that similar cooperation of 3' and 5' nucleotides is also required for signaling mRNA transcription. By incorporating these 3' and 5' nucleotides into the transcriptionally silent BUNV anti-genome, a BUNV segment that performed ambisense transcription was generated. This work sheds light on a fundamental process of bunyavirus molecular biology and identifies a potential strategy for generating viable variants of BUNV capable of expressing additional proteins.

Live Visualization of Alternative Viral Replication Origins

Adeno-associated virus (AAV) replication origins have previously been identified in the inverted terminal repeats and, recently, within the p5 promoter. Glauser et al. (p. 12218-12230) demonstrate the simultaneous and independent activity of these two alternative replication origins at the single cell level by using multicolor fluorescence live-cell imaging, suggesting that both replication origins contribute to the AAV life cycle. Furthermore, the authors assess the differential affinity of the essential AAV replication protein, Rep, for the two alternative replication origins both in vitro and in live cells and identify this as a potential mechanism to control the replicative and promoter activities of p5.

Birnavirus Structural Peptides Involved in Assembly and Membrane Translocation

The capsid of infectious bursal disease virus is constituted by a single protein, VP2, and four disordered peptides, all derived from a precursor, pVP2. Chevalier et al. (p. 12253-12263) show that two of these peptides, pep11 and pep46, control virus assembly and cell entry. This work has implications for understanding the morphogenesis of complex viral capsids and the entry process of nonenveloped viruses.

An Apoptosis Inhibitor Gene Can Replace the HSV-1 LAT

Latency-associated transcript (LAT)-null mutants of herpes simplex virus type 1 (HSV-1) have a significantly reduced reactivation phenotype. Jin et al. (p. 12286-12295) now show that an HSV-1 mutant containing the unrelated baculovirus inhibitor of apoptosis protein (cpIAP) gene in place of LAT has a wild-type reactivation phenotype in mice. Thus, an unrelated apoptosis inhibitor can functionally substitute for LAT and enhance HSV-1 reactivation. This finding is consistent with previous reports that LAT has anti-apoptosis activity and suggests that LAT enhances HSV-1 reactivation in mice via blockade of apoptosis.

EBV-Encoded Small RNA (EBER) Inhibits Fas-Mediated Apoptosis by Blocking the PKR Pathway

EBER is Epstein-Barr virus (EBV)-encoded non-polyadenylated small RNA, which is highly expressed in cells latently infected with EBV. Nanbo et al. (p. 12280-12285) show that EBER binds dsRNA-dependent protein kinase (PKR), an interferon (IFN)-inducible serine/threonine kinase, inhibits its phosphorylation, and confers resistance to Fas-mediated apoptosis in EBV-infected epithelial cells. These findings highlight an interaction between Fas-induced apoptotic signals and the PKR pathway and underline a role for EBER in EBV-associated malignancies.

Pathogenic Rabies Virus Evades Host Innate Immune Responses in the CNS

It is not fully understood how rabies virus (RV) induces fatal encephalomyelitis and, in particular, what host responses are induced. Using the Affymetrix mouse whole genome array, Wang et al. (p. 12554-12565) compared host gene expression in mice infected with wild-type RV strain SHBRV with those infected with attenuated strain B2C. Attenuated RV induced expression of genes involved in innate immunity, especially those related to the IFN-/ß signaling pathway and inflammatory chemokines. Interestingly, many of these genes were not up-regulated in mice infected with wt SHBRV. These findings suggest that pathogenic RV evades host innate immune and antiviral responses, allowing rapid dissemination within the CNS.

Cytokine Balance Regulates Cell-to-Cell HIV-1 Infection at the Level of the Placental Barrier

Cells at the maternal-fetal interface secrete soluble factors that may participate in controlling HIV-1 transmission from mother to fetus. Derrien et al. (p. 12304-12310) show that placental chemokines (RANTES and MIP-1ß) and cytokines (TNF- and IL-8) decrease and increase, respectively, viral production in placental trophoblast barriers inoculated with HIV-1-infected cells. This study highlights the importance of cellular activation induced after cell-to-cell contact as a potent mechanism of HIV-1 dissemination across the placental barrier and shows that local cytokines and chemokines can regulate the amount of virus produced thereupon.

Candidate Vaccine for Highly Pathogenic Influenza Virus (H7N7)

Vaccines are effective against epidemic human influenza, but development of effective vaccines against potentially pandemic influenza viruses (e.g., hemagglutinin subtypes H5, H7, and H9) is fraught with problems. Using reverse genetics technology, de Wit et al. (p. 12401-12407) produced a candidate vaccine against the highly pathogenic avian influenza virus A/Netherlands/219/03 (H7N7), based on a related low virulence virus from a wild duck. When administered to mice with immune-stimulating complexes (ISCOMs) as adjuvant, this subunit vaccine provided protection from lethal infection with the highly pathogenic virus. This strategy allows vaccine development well ahead of pandemic threats posed by novel influenza virus subtypes.

HMPV Live Vaccine Candidates: SH, G, and M2-2 Proteins Are Nonessential

Human metapneumovirus (HMPV), a paramyxovirus first described in 2001, is now recognized to account for about 5 to 10% of early-childhood respiratory infections requiring hospitalization. Biacchesi et al. (p. 12608-12613) used reverse genetics to generate HMPV lacking two nonprotective envelope glycoproteins, SH or G, or the RNA polymerase regulatory protein M2-2. Evaluation of these live vaccine candidates in a nonhuman primate model showed that all three proteins were dispensable for in vivo replication. The G and M2-2 deletion viruses were highly attenuated, immunogenic, and protective against HMPV challenge and thus represent promising vaccine candidates for clinical evaluation.

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