Articles of Significant Interest Selected from This Issue by the Editors
Ebola Virus Glycoproteins and Endothelial Cell Function
Ebola virus causes a severe hemorrhagic fever in humans that involves vascular instability and dysregulation. The Ebola virus glycoproteins have been implicated as pathogenic determinants. However, the role of the major soluble glycoprotein sGP has not been defined. Using a novel, highly sensitive method, impedance spectroscopy, Wahl-Jensen et al. (p. 10442-10450) show that the transmembrane GP causes endothelial activation and decreases endothelial barrier function, but soluble sGP does not. Unexpectedly, sGP reverses TNF-α-induced disruption of endothelial barrier function, indicating a protective role for sGP that might serve as an anti-inflammatory weapon of the virus.
Restricted Tropism of Vaccinia Virus and Insights into Its Cellular Receptor
Based on studies documenting a broad tropism for infection of diverse types of cultured cells, vaccinia virus is thought to employ a ubiquitously expressed cellular receptor. However, Chahroudi et al. (10397-10407) demonstrate that when primary hematolymphoid target cells are examined for susceptibility to infection, the tropism of vaccinia virus is restricted to specific cell lineages that constitute key antigen-presenting and immune effector cells. The cellular receptor for vaccinia virus binding induced upon activation of primary T cells differs from that found on cell lines in culture. These data provide a biologic basis for the identification of poxvirus receptors and contribute to our understanding of poxvirus pathogenesis and immunogenicity.
A Single Amino Acid Substitution Confers Trypsin-Independent Growth of Human Metapneumovirus
Nearly all previously reported strains of human metapneumovirus (hMPV) contain an RQSR sequence at the putative cleavage site of the fusion (F) protein and require trypsin for growth in cell culture. Schickli et al. (10678-10689) report two strains, hMPV/NL/1/99 and hMPV/NL/1/00, that contain the sequence RQPR and do not require trypsin. The results suggest that the single substitution S101P facilitates trypsin-independent cleavage of F protein in cell culture. These trypsin-independent strains of hMPV should greatly facilitate development of attenuated hMPV vaccine candidates.
Peeling Back the Petals of an IRES
Assembly of the ribosome on the hepatitis C virus IRES requires translation machinery and cellular proteins such as La, Ptb, and Pcbp2. Rosenfeld and Racaniello (10126-10137) demonstrate that Saccharomyces cerevisiae possesses all of the proteins necessary for internal initiation dependent on this viral IRES. The establishment of an in vivo functional assay will facilitate the identification of proteins required for translation mediated by the IRES of hepatitis C virus.
The Portal Is Involved in Initiation of Herpes Simplex Virus Capsid Assembly
For more than 30 years virologists have puzzled over the question of how an icosahedral virus capsid can be assembled in such a way that one of the 12 vertices is chemically distinct from the other 11. Such a “unique vertex” is found in herpesvirus capsids and the capsids of dsDNA bacteriophages. In 1978, it was suggested on theoretical grounds that the unique structure, the portal, might be involved in initiation of capsid formation. Newcomb et al. (10540-10546) now describe experiments demonstrating that this is indeed the case. Using an in vitro system for assembly of herpes simplex virus capsids, portal-containing capsids were observed to form only if the portal is present at the outset of the assembly process. A delay in portal addition results in formation of capsids lacking portals. The results show that the portal must be incorporated as assembly is initiated and cannot be added thereafter.
A Central Role for Notch Transcription Factor RBP-Jκ/CBF1 in EBV-Mediated B-Lymphocyte Proliferation
Epstein-Barr virus (EBV) latency-associated nuclear proteins EBNA2, EBNA3A, and EBNA3C are critical for EBV-infected B-lymphocyte proliferation and regulate transcription through association with RBP-Jκ/CBF1. Mutations in the EBNA2 domain that mediates RBP-Jκ/CBF1 association are null for B-lymphocyte proliferation. Maruo et al. (10171-10179) have discovered that EBNA3A mutations in domains that affect RBP-Jκ/CBF1-mediated transcription are also null for lymphocyte proliferation, whereas deletion of most other EBNA3A domains result in wild-type or intermediate lymphocyte growth. Thus, evidence mounts that regulation of Notch pathway gene transcription is central to EBV-infected lymphocyte proliferation.
Early Steps in Virus Infection Activate IFN-α/β Production in Myeloid Dendritic Cells
Myeloid dendritic cells (mDCs) are capable of producing IFN-α/β in response to replication-incompetent virus, suggesting that these cells are sentinels of early virus infection events. Hidmark et al. (10376-10385) have investigated the viral functions and cellular pathways required for IFN-α/β induction in murine mDCs. The data show that mDCs produce IFN-α/β via a MyD88-independent, entry-dependent pathway that involves IRF-3. This mechanism differs from the TLR7/MyD88-dependent, fusion-independent production of INF-α activated by single-stranded viral RNA genomes described for plasmacytoid DCs (pDCs). These results suggest that mDCs and pDCs respond to incoming virus via nonoverlapping pathways.
Gamma Interferon Blocks Multiple Steps in HSV-1 Reactivation from Latency
The reactivation of HSV-1 from a latent state in sensory neurons can be blocked by CD8+ T cells. Decman et al. (10339-10347) demonstrate that the CD8+ T-cell cytokine gamma interferon can block HSV-1 reactivation at multiple steps in the viral gene expression cascade following the initiation of reactivation from latency. An intriguing finding was that reactivation could be halted at a stage subsequent to expression of viral late genes. These results suggest a larger than anticipated window of opportunity for CD8+ T cells to intervene in the reactivation process responsible for recurrent herpetic disease.
Molecular Machines Assembled by Paramyxovirus V Proteins
Rubulaviruses inhibit interferon in part by V protein-mediated assembly of ubiquitin ligase complexes that target STAT proteins. The V-dependent degradation complex (VDC) contains cellular STATs, DDB1, Cul4A, and Roc1. Ulane et al. (10180-10189) define differential requirements for cellular factors in STAT targeting and demonstrate that V proteins engage host factors in separate subcomplexes. V proteins were found to oligomerize via their C-terminal zinc-binding domain and to self-assemble into spherical particles. These particles are hypothesized to form a catalytic surface for ubiquitination and possibly other reactions mediated by V proteins. This report highlights a novel aspect of V protein biochemistry used to engage and dismantle host innate immunity.
Poxviruses Hijack Cell-Cycle Control Mechanisms
Many tumor viruses alter the cell-cycle control machinery when they transform cells. The study by Johnston et al. (10750-10763) shows that even acute infection by a poxvirus can result in specific alterations of cell-cycle control that favor viral replication. The myxoma virus host range gene M-T5 facilitates the G0/G1 cell-cycle checkpoint progression of infected cells, whereas a virus lacking this gene arrests at this checkpoint and initiates apoptosis. The mechanism of this control resides in the capacity of M-T5 to alter the host Cullin-1 ubiquitin ligase complex, and thereby constitutively degrade the cyclin-dependant kinase inhibitor p27/Kip-1. Thus, poxviruses can short-circuit the induction of a default apoptotic response associated with inappropriate cell-cycle arrest in response to viral infection.
The Mutant Spectrum Does It All
The prototypical arenavirus lymphocytic choriomeningitis virus (LCMV) is highly sensitive to 5-fluorouracil-induced mutagenesis, leading to fitness loss and virus extinction. Grande-Pérez et al. (10451-10459) have found that LCMV pre-extinction populations can regain infectivity in the absence of mutagen and, despite dramatic fitness variations, the virus maintains an invariant consensus sequence. The results support a lethal defection mechanism for virus extinction in which mutant spectra with a limited number of mutations are enriched in defective genomes that can mediate the transition into error catastrophe.
- American Society for Microbiology
