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Background Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)–positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. Results Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody–negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. Conclusions We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. ClinicalTrials.gov registration NCT04358549. [ABSTRACT FROM AUTHOR]

Background Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. Methods In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Results Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription–polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, −3.6 day*log10 copies/mL [95% confidence interval {CI}, −7.1 to −0.1]; 600 mg group, −4.5 [95%CI −8.0 to −1.0]; and combination group, −8.6 [95% CI, −12.0 to −5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Conclusions Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. Clinical Trials Registration NCT02342249, 2014-004068-39, and CR107745. [ABSTRACT FROM AUTHOR]

Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial pass-aging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated. [ABSTRACT FROM AUTHOR]

The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations. [ABSTRACT FROM AUTHOR]

Background. Herpes simplex virus type 1 (HSV-1) infects >70% of the United States population. We identified a 3-megabase region on human chromosome 21 containing 6 candidate genes associated with herpes simplex labialis (HSL, ''cold sores''). Methods. We conducted single nucleotide polymorphism (SNP) scans of the chromosome 21 region to define which of 6 possible candidate genes were associated with cold sore frequency. We obtained the annual HSL frequency for 355 HSV-1 seropositive individuals and determined the individual genotypes by SNPlex for linkage analysis and parental transmission disequilibrium testing (ParenTDT). Results. Two-point linkage analysis showed positive linkage between cold sore frequency and 2 SNPs within the C21orf91 region, 1 of which is nonsynonymous. ParenTDT analysis revealed a strong association between another C21orf91 SNP, predicted to lie in the 3# untranslated region, and frequent HSL (P = .0047). C21orf 91 is a predicted open reading frame of unknown function that encodes a cytosolic protein. Conclusions. We evaluated candidate genes in the cold sore susceptibility region using fine mapping with 45 SNP markers. 2 complementary techniques identified C21orf91 as a gene of interest for susceptibility to HSL. We propose that C21orf91 be designated the Cold Sore Susceptibility Gene-1 (CSSG1). [ABSTRACT FROM AUTHOR]

Background. Recent studies demonstrate that long palate, lung, and nasal epithelium clone 1 protein (LPLUNC1) is involved in immune responses to Vibrio cholerae, and that variations in the LPLUNC1 promoter influence susceptibility to severe cholera in humans. However, no functional role for LPLUNC1 has been identified Metods. We investigated the role of LPLUNC1 in immune responses to V. cholerae, assessing its affect on bacterial growth and killing and on innate inflammatory responses to bacterial outer membrane components, including purified lipopolysaccharide (LPS) and outer membrane vesicles. We performed immunostaining for LPLUNC1 in duodenal biopsies from cholera patients and uninfected controls. Results. LPLUNC1 decreased proinflammatory innate immune responses to V. cholerae and Escherichia coli LPS. The effect of LPLUNC1 was dose-dependent and occurred in a TLR4-dependent manner. LPLUNC1 did not affect lipoprotein-mediated TLR2 activation. Immunostaining demonstrated expression of LPLUNC1 in Paneth cells in cholera patients and controls Conclusions. Our results demonstrate that LPLUNC1 is expressed in Paneth cells and likely plays a role in modulating host inflammatory responses to V. cholerae infection. Attenuation of innate immune responses to LPS by LPLUNC1 may have implications for the maintenance of immune homeostasis in the intestine [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals.Methods: Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection.Results: Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb (201) bound within the receptor-binding domain at aa 490-510, and the other MAb (68) bound externally to the domain at aa 130-150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection.Conclusions: Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region. [ABSTRACT FROM AUTHOR]

Background. Although a considerable amount of research has gone into the study of the role of bactericidal versus bacteriostatic antimicrobial agents in the treatment of different infectious diseases, there is no accepted standard of practice. Methods. A panel of infectious diseases specialists reviewed the available literature to try to define specific recommendations for clinical practice. Results. In infections of the central nervous system, the rapidity with which the organism is killed may be an important determinant, because of the serious damage that may occur during these clinical situations. The failure of bacteriostatic antibiotics to adequately treat endocarditis is well documented, both in human studies and in animal models. Conclusion. The bulk of the evidence supports the concept that, in treating endocarditis and meningitis, it is important to use antibacterial agents with in vitro bactericidal activity. This conclusion is based on both human and animal data. The data to support bactericidal drugs' superiority to bacteriostatic drugs do not exist for most other clinical situations, and animal models do not support this concept in some situations. Clinicians should be aware that drugs that are bacteriostatic for one organism may in fact be bactericidal for another organism or another strain of the same organism. [ABSTRACT FROM AUTHOR]

Prokaryotic and eukaryotic cells respond to a variety of stress conditions by increasing the synthesis of a family of proteins collectively known as heat-shock proteins (HSP). One of these, a 65-kDa HSP that is highly conserved in many bacteria, is a major target of the immune response to mycobacteria. A γδ T cell clone from a healthy donor that recognizes not only the 65-kDa mycobacterial HSP but also the recombinant human homologue of this HSP protein was raised. Like ocfJ T cell clones, which recognize mycobacterial HSP, the clone requires antigen-presenting cells for antigen-induced proliferation and can also bedirectly activated via receptor cross-linking through CD3 or the δ chain of the γδ T cell receptor. These data suggest that the induction of a γδ T cell response by bacterial antigens could lead to the expansion of cells that respond to autologous proteins and, therefore, may result in the development of autoimmunity. [ABSTRACT FROM PUBLISHER]

Coxsackie B viruses interact with two putative cell surface receptor molecules. Experiments with prototype laboratory strains suggest that all 6 coxsackie B serotypes interact with a 46-kDa protein recognizedby the monoclonalantibody RmcB, whereas CB1, CB3, and CBSmay also bind to decay accelerating factor. Antireceptor monoclonal antibodies were used to study interactions between low-passage clinical coxsackie B virus isolates and the two receptors. In contrast to observations made with single prototype strains, these data indicate that receptor use by clinical isolates is not strictly related to serotype and that even prototype strains with different passage histories may differ in receptor use. Within a given serotype, variation exists in the capacity of individual virus isolates to bind to specific receptors, and variants with altered receptor specificity may arise during infection in humans and in tissue culture. [ABSTRACT FROM PUBLISHER]

Toll-like receptors (TLRs)-and their associated signal-trans-ducing proteins-on the surface of cells have been demo nstrated to account for most, if not all, of the events associated with bacterial sepsis. Using human cells expressing different TLRs, we demo nstrated that the interaction between TLR2 and herpes simplex virus (HSV)-1-2 leads to the production of cytokines. Using peripheral-blood mononuclear cells, we tested the ability of cells from people of different age groups to make cytokines in response to HSV. An examination of the host responses of neonates to HSV indicates that, rather than producing less interleukin-6 and interleukin-8 in response to HSV than adults do, neonates produce more of these cytokines than adults do. This may explain the sepsis syndrome that is seen with HSV (and other virus infections) in neonates. [ABSTRACT FROM AUTHOR]

The article discusses the significant role that toll-like receptors (TLRs) play in the human immune response mechanism consisting of pattern recognition proteins that recognize pathogen associated molecular patterns (PAMPs). It relates that TLRs function in the human immune response system as identifier of viruses, bacteria, fungi, and parasites as well as on the activation of the production cytokines that leads to local or systemic inflammation. Moreover, it cites a study conducted by Bochud P-Y and colleagues about genetic polymorphisms that illustrated how genetic predispositions define human response to infections.