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SPOTLIGHT

Articles of Significant Interest Selected from This Issue by the Editors

The viral proteins governing the initiation of RNA synthesis by hepatitis C virus (HCV) are poorly defined. Binder et al. (p. 5270-5283) report a system based on chimeric HCV genomes of two different viral isolates, allowing the analysis of viral proteins and cis-acting elements involved in RNA synthesis. The study demonstrates that the helicase and nonstructural proteins 5A and 5B are required for progeny positive-strand initiation. Chimeras between closely related viral subtypes might provide a general strategy to define the initiation complex of positive-strand RNA viruses.

The Host Complement Cascade Contributes to Alphavirus-Induced Arthritis

Alphaviruses, such as Ross River virus (RRV) and Chikungunya virus, cause outbreaks of infectious arthritis in humans. Morrison et al. (p. 5132-5143) provide evidence that the host complement cascade is activated in the joints of persons suffering from RRV-induced polyarthritis. Using a mouse model of RRV-induced arthritis/myositis, the authors demonstrate that complement plays an essential role in the destructive phase of the disease but is not required for the recruitment of inflammatory cells into affected tissues. These findings suggest that the complement cascade may be a target for therapeutic intervention during alphavirus-induced arthritis.

Delivery System Improves Plasmid DNA Vaccine Performance In Vivo

Despite promising results in preclinical immunogenicity studies, plasmid DNA (pDNA) vaccines delivered by standard intramuscular injection have generally been incapable of inducing robust antigen-specific immune responses. Luckay et al. (p. 5257-5269) show that rhesus macaques immunized by intramuscular injection with a multiantigen pDNA vaccine in combination with in vivo electroporation demonstrated a 10-fold increase in vaccine-specific T-cell responses and a 100-fold increase in vaccine-specific antibody responses relative to macaques receiving a 5-fold-higher dose of pDNA in the absence of in vivo electroporation. These results have important implications for the successful clinical development of plasmid DNA as a stand-alone vaccine platform.

Cross-Clade Potency of RNA Aptamer Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

RNA aptamers that bind reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1) are potent inhibitors of RT enzymatic activity and suppress viral replication when expressed in cultured lymphoid cell lines. Held et al. (p. 5375-5384) explored the capacity of these aptamers, which were selected against RT from a subtype B isolate, to inhibit RTs from other HIV and simian immunodeficiency virus clades. Cross-clade potency varied with RNA structure. Surprisingly, a single lysine/arginine polymorphism in the p66 thumb domain conferred resistance to one class of RNA pseudoknots but not to a related class. These results have implications for gene therapy and diagnostic applications that exploit target recognition by nucleic acid aptamers.

A New Giraffe Coronavirus Is Genetically and Biologically Related to Bovine Coronaviruses and Is Transmissible to Cattle

Interspecies transmission of coronaviruses (CoV) can expand viral host range and contribute to new epidemics of disease. Hasoksuz et al. (p. 4981-4990) documented interspecies transmission of a CoV and a new wildlife reservoir. A CoV isolated from a captive giraffe (GiCoV) with diarrhea replicated in HRT-18 cells and caused diarrhea in a gnotobiotic calf. Sequencing of the complete GiCoV genome revealed a close relationship (>99% amino acid [aa] identity) to bovine CoVs but with a 5-aa deletion in the hypervariable region of the GiCoV S1 subunit, a region associated with CoV pathogenicity. Point mutations in the structural proteins were conserved, whereas most in the nonstructural proteins were unique to GiCoV. This work confirms the existence of a bovine-like CoV transmissible to cattle from a wild ruminant but with certain distinctive genetic properties.

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