Functional characterization of the alphavirus TF protein.

Alphavirus dogma has long dictated the production of a discrete set of structural proteins during infection of a cell: capsid, pE2, 6K, and E1. However, bioinformatic analyses of alphavirus genomes (A. E. Firth, B. Y. Chung, M. N. Fleeton, and J. F. Atkins, Virol. J. 5:108, 2008) suggested that a ribosomal frameshifting event occurs during translation of the alphavirus structural polyprotein. Specifically, a frameshift event is suggested to occur during translation of the 6K gene, yielding production of a novel protein, termed transframe (TF), comprised of a C-terminal extension of the 6K protein in the -1 open reading frame (ORF). Here, we validate the findings of Firth and colleagues with respect to the production of the TF protein and begin to characterize the function of TF. Using a mass spectrometry-based approach, we identified TF in purified preparations of both Sindbis and Chikungunya virus particles. We next constructed a panel of Sindbis virus mutants with mutations which alter the production, size, or sequence of TF. We demonstrate that TF is not absolutely required in culture, although disrupting TF production leads to a decrease in virus particle release in both mammalian and insect cells. In a mouse neuropathogenesis model, mortality was <15% in animals infected with the TF mutants, whereas mortality was 95% in animals infected with the wild-type virus. Using a variety of additional assays, we demonstrate that TF retains ion-channel activity analogous to that of 6K and that lack of production of TF does not affect genome replication, particle infectivity, or envelope protein transit to the cell surface. The TF protein therefore represents a previously uncharacterized factor important for alphavirus assembly.

Supartz (Sodium Hyaluronate) for the Treatment of Knee Osteoarthritis: A Review of Efficacy and Safety.

As concerns about the safety of systemic oral pharmacologic treatments for knee osteoarthritis (OA) mount, clinicians have increased the use of intra-articular hyaluronic acid (IA-HA) in managing mild-to-moderate knee OA. Supartz (sodium hyaluronate; Seikagaku Corporation, Tokyo, Japan) is the first IA-HA product to be approved in the world and has the longest history of global use. In this review, we summarize evidence supporting Supartz efficacy and safety, including data from pivotal clinical trials that resulted in approval of Supartz in the United States and Japan, the safety of single and repeated courses of Supartz, and Supartz efficacy using objective outcomes and in special populations. There is strong evidence that single 5-week courses of Supartz provide clinically meaningful reductions in pain and improved function for up to 6 months without risk of serious side effects or complications. Repeated courses of Supartz are as safe as single courses and have an extremely low risk of infection. Findings from promising initial studies, which suggest that Supartz may improve muscle strength, gait pattern, and balance, should be confirmed in randomized controlled trials.