Can We “Hedge” against the Development of Antiviral Resistance among Pandemic Influenza Viruses?

David K. Shay and Benjamin Ridenhour discuss a modeling study predicting that stockpiling a secondary antiviral for use early in a flu pandemic can forestall resistance to the primary stockpiled drug

Vaccines and Antiviral Drugs in Pandemic Preparedness

Controlling a pandemic with vaccine and antiviral drugs will require a coordinated international approach to determine how the least amount of virus can immunize the largest segment of a population

Resolution of a common RNA sequencing ambiguity by terminal deoxynucleotidyl transferase

One of the more common ambiguities which arise when using reverse transcriptase and dideoxynucleotide-chain termination to sequence RNA is a radioactive band of cDNA that extends over all four lanes on a sequencing gel. The adjacent sequences both above and below the band are not affected. Assuming then, that these ambiguities are caused by the termination of the DNA polymerase activity of reverse transcriptase for reasons other than the insertion of a dideoxynucleotide in the growing cDNA chain, terminal deoxynucleotidyl transferase should be able to continue to add deoxynucleotides to these products after the sequencing reaction is complete. It does, clearing the improperly terminated cDNA from these pileup sites, revealing the correct sequence. This technique can also be used to identify the template RNA's 5'-terminal base, although far more units of terminal deoxynucleotidyl transferase are required.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26058/1/0000132.pd

Oseltamivir-Resistant Influenza Viruses A (H1N1) during 2007–2009 Influenza Seasons, Japan

Prevalence of these viruses increased during the 2008–09 season

Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007–08

Resistance was not associated with oseltamivir use or more severe disease

Oseltamivir in seasonal influenza: cumulative experience in low- and high-risk patients

Seasonal influenza viruses cause annual disease epidemics that affect individuals at low and high risk for secondary illnesses. Influenza vaccines are widely used in high-risk patients to prevent infection, but the protection afforded varies by population; uptake is also limited in some groups. Antiviral drugs for influenza are now readily available. Oseltamivir is the most widely used antiviral for the treatment and prophylaxis of seasonal influenza, and its efficacy and safety are now well established in a variety of populations. In addition to decreasing the severity and duration of the symptoms of influenza, clinical and epidemiological studies demonstrate that oseltamivir significantly reduces the frequency of secondary illnesses and exacerbation of underlying conditions; survival is also significantly improved in seriously ill patients who are hospitalized with severe influenza. Resistant viruses are isolated with a low frequency during oseltamivir treatment (0.33% in adults and 4.0% in children among almost 2000 oseltamivir-treated patients enrolled onto Roche-sponsored clinical trials of oseltamivir treatment during the oseltamivir development programme). However, an oseltamivir-resistant influenza A (H1N1) virus emerged in Europe during the 2007–08 season and circulated in the southern and northern hemispheres in 2008–09. No link with oseltamivir usage could be detected, and the clinical impact of these viruses was limited. Oseltamivir-susceptible pandemic (H1N1) 2009 viruses now predominate in many countries. Oseltamivir is generally well tolerated, with a similar adverse event profile to placebo

Sequence comparison of wild-type and cold-adapted B/Ann Arbor/1/66 influenza virus genes

Consensus sequences for both wt and ca B/Ann Arbor/1 /66 viral PB2, PB1, PA, NP, M, and NS genes were directly determined from vRNA using a combination of chemical and chain-termination sequencing methods. There were 105 sites of difference between the wt and ca sets of these six RNA genes. The differences resulted in 26 amino acid substitutions distributed over the six proteins. The sequence changes were compared to the sequences of other known influenza type B wt viruses to pinpoint those changes that were unique to the ca B/Ann Arbor/1/66 virus. Of the 26 amino acid differences, only 11 were unique to the cold-adapted virus. These unique sites were distributed among five of the six genes. The NS protein had no amino acid substitutions. The sequence changes are discussed in terms of their probable mode of origin and selection, and in terms of their importance to the cold-adapted, temperature-sensitive, and attenuation phenotypes of ca B/AA/1 /66 virus. The sequence and organization of the PB2 gene and predicted protein are also given. The PB2 gene was 2396 nucleotides long, and it encoded a predicted protein of 770 amino acids with a molecular weight of 88,035 Da for the wt virus and 88,072 Da for the ca virus. Both proteins were predominantly hydrophilic, and each had an overall charge of +24.5 at pH 7.0.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27362/1/0000387.pd

Research Liaisons: the next layer of Facilitation

This item includes a conference paper and the accompanying presentation given at the conference. The presentation was prerecorded.Research productivity has been greatly enhanced by Research Computing Facilitation teams to help researchers maximize their use of advanced cyberinfrastructure. However, researchers have more technology needs than just advanced cyberinfrastructure, such as data management and instrument device support. To address this, the Academic Engagement team in Michigan Medicine added Research Liaisons as another layer of human support on top of the Facilitation team. The Liaisons are relationship builders. They are assigned to departments to build deep relationships with them and start proactively addressing labs’ technology needs. They also build relationships with other teams, notably enterprise storage, enterprise networking, and research core facilities. These relationships allow Liaisons to provide a connective tissue between the researchers and IT teams.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170574/1/McCaffrey et al. - 2021 - Research Liaisons the next layer of Facilitation.pdfDescription of McCaffrey et al. - 2021 - Research Liaisons the next layer of Facilitation.pdf : Main articleSEL

IL‐17E (IL‐25) and IL‐17RB promote respiratory syncytial virus‐induced pulmonary disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141555/1/jlb0809.pd

Oseltamivir–Resistant Pandemic H1N1/2009 Influenza Virus Possesses Lower Transmissibility and Fitness in Ferrets

The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007–2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the transmissibility of a closely matched pair of pandemic H1N1/2009 clinical isolates, one oseltamivir-sensitive and one resistant, in the ferret model. The resistant H275Y mutant was derived from a patient on oseltamivir prophylaxis and was the first oseltamivir-resistant isolate of the pandemic virus. Full genome sequencing revealed that the pair of viruses differed only at NA amino acid position 275. We found that the oseltamivir-resistant H1N1/2009 virus was not transmitted efficiently in ferrets via respiratory droplets (0/2), while it retained efficient transmission via direct contact (2/2). The sensitive H1N1/2009 virus was efficiently transmitted via both routes (2/2 and 1/2, respectively). The wild-type H1N1/2009 and the resistant mutant appeared to cause a similar disease course in ferrets without apparent attenuation of clinical signs. We compared viral fitness within the host by co-infecting a ferret with oseltamivir-sensitive and -resistant H1N1/2009 viruses and found that the resistant virus showed less growth capability (fitness). The NA of the resistant virus showed reduced substrate-binding affinity and catalytic activity in vitro and delayed initial growth in MDCK and MDCK-SIAT1 cells. These findings may in part explain its less efficient transmission. The fact that the oseltamivir-resistant H1N1/2009 virus retained efficient transmission through direct contact underlines the necessity of continuous monitoring of drug resistance and characterization of possible evolving viral proteins during the pandemic