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Infectious Disease Clinics of North... Sep 2019Approximately 20% of people with HIV in the United States prescribed antiretroviral therapy are not virally suppressed. Thus, optimal management of virologic failure has... (Review)
Review
Approximately 20% of people with HIV in the United States prescribed antiretroviral therapy are not virally suppressed. Thus, optimal management of virologic failure has a critical role in the ability to improve viral suppression rates to improve long-term health outcomes for those infected and to achieve epidemic control. This article discusses the causes of virologic failure, the use of resistance testing to guide management after failure, interpretation and relevance of HIV drug resistance patterns, considerations for selection of second-line and salvage therapies, and management of virologic failure in special populations.
Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Disease Management; Drug Resistance, Viral; HIV; HIV Infections; Humans; Sustained Virologic Response; Treatment Failure; United States
PubMed: 31255384
DOI: 10.1016/j.idc.2019.05.004 -
The Journal of Allergy and Clinical... Aug 2021Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity... (Clinical Trial)
Clinical Trial
BACKGROUND
Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known.
OBJECTIVE
We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease.
METHODS
Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids.
RESULTS
Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes.
CONCLUSION
ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.
Topics: Antigens, Neoplasm; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Infant; Inflammation; Male; Primary Immunodeficiency Diseases; Virus Diseases; Exome Sequencing
PubMed: 33872655
DOI: 10.1016/j.jaci.2021.03.045 -
Bioinformation 2020There have been over five million cases of infection with the second Corona virus to induce SARS (SARS-CoV2) and close to half a million deaths worldwide since the first...
There have been over five million cases of infection with the second Corona virus to induce SARS (SARS-CoV2) and close to half a million deaths worldwide since the first report of Corona Virus Disease in late December 2019 (CoViD-19). Over two million CoViD-19 patients have recovered. The factors and variables that lead certain CoViD-19 patients to survive this otherwise aggressive and lethal viral infection are intensely researched, as is the development of productive anti-virals and of safe and effective vaccines. Several hypotheses invoke putative mutations of the ss-positive RNA SARS-CoV2 virus to states of stronger or weaker virulence and lethality. Other hypotheses propose that the patient's status of immunity, vitamin D level, Zinc deficiency or other physiological parameters determine how any given patient will effectively weather the viremia and the consequential multi-symptomatic CoViD-19. The initial cause - causa prima - underlying all the symptoms of CoViD-19 is infection of the host human cell by SARS-CoV2. The virus spike (S) protein finds its binding site, ACE2, widely distributed in all cells and tissues that potentially proffer CoViD-19 pathology. S consists of two subunits, S1 and S2, which are cleaved by the widely expressed transmembrane protease serine 2 (TMPRSS2) before the virus fuses to the plasma membrane and infects the cell. Current trends show that variant alleles resulting from single nucleotide polymorphisms (SNPs) of ACE2, and genetic variants of TMPRSS2, with putative distinct affinities for S clip, may determine a complex multi-factorial spectrum of SARS-CoV2 virulence across patients, and predict CoViD-19 susceptibility.
PubMed: 32994673
DOI: 10.6026/97320630016501 -
Nature Sep 2022The RNA genome of SARS-CoV-2 contains a 5' cap that facilitates the translation of viral proteins, protection from exonucleases and evasion of the host immune response....
The RNA genome of SARS-CoV-2 contains a 5' cap that facilitates the translation of viral proteins, protection from exonucleases and evasion of the host immune response. How this cap is made in SARS-CoV-2 is not completely understood. Here we reconstitute the N7- and 2'-O-methylated SARS-CoV-2 RNA cap (GpppA) using virally encoded non-structural proteins (nsps). We show that the kinase-like nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain of nsp12 transfers the RNA to the amino terminus of nsp9, forming a covalent RNA-protein intermediate (a process termed RNAylation). Subsequently, the NiRAN domain transfers the RNA to GDP, forming the core cap structure GpppA-RNA. The nsp14 and nsp16 methyltransferases then add methyl groups to form functional cap structures. Structural analyses of the replication-transcription complex bound to nsp9 identified key interactions that mediate the capping reaction. Furthermore, we demonstrate in a reverse genetics system that the N terminus of nsp9 and the kinase-like active-site residues in the NiRAN domain are required for successful SARS-CoV-2 replication. Collectively, our results reveal an unconventional mechanism by which SARS-CoV-2 caps its RNA genome, thus exposing a new target in the development of antivirals to treat COVID-19.
Topics: Antiviral Agents; COVID-19; Catalytic Domain; Guanosine Diphosphate; Humans; Methyltransferases; Nucleotidyltransferases; Protein Domains; RNA Caps; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Viral Proteins; COVID-19 Drug Treatment
PubMed: 35944563
DOI: 10.1038/s41586-022-05185-z -
Journal of Virology Jan 2024In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight...
In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.
Topics: Humans; Containment of Biohazards; COVID-19; United States; Viruses; Virology; Biomedical Research
PubMed: 38168672
DOI: 10.1128/jvi.01791-23 -
Trends in Microbiology Nov 2020While conventional in vitro culture systems and animal models have been used to study the pathogenesis of viral infections and to facilitate development of vaccines and... (Review)
Review
While conventional in vitro culture systems and animal models have been used to study the pathogenesis of viral infections and to facilitate development of vaccines and therapeutics for viral diseases, models that can accurately recapitulate human responses to infection are still lacking. Human organ-on-a-chip (Organ Chip) microfluidic culture devices that recapitulate tissue-tissue interfaces, fluid flows, mechanical cues, and organ-level physiology have been developed to narrow the gap between in vitro experimental models and human pathophysiology. Here, we describe how recent developments in Organ Chips have enabled re-creation of complex pathophysiological features of human viral infections in vitro.
Topics: Animals; Humans; Microfluidics; Organ Culture Techniques; Virology; Virus Diseases; Virus Physiological Phenomena; Viruses
PubMed: 32674988
DOI: 10.1016/j.tim.2020.06.005 -
Virology Apr 2023
Topics: Nanotechnology; Virology
PubMed: 36893501
DOI: 10.1016/j.virol.2023.02.015 -
Journal of Hepatology Mar 2020Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV... (Review)
Review
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Topics: Alanine Transaminase; Antiviral Agents; Biomarkers; Clinical Trials, Phase III as Topic; Coinfection; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Research Design; Sustained Virologic Response
PubMed: 31730789
DOI: 10.1016/j.jhep.2019.11.003 -
Nature Jan 2024Bacteria encode hundreds of diverse defence systems that protect them from viral infection and inhibit phage propagation. Gabija is one of the most prevalent anti-phage...
Bacteria encode hundreds of diverse defence systems that protect them from viral infection and inhibit phage propagation. Gabija is one of the most prevalent anti-phage defence systems, occurring in more than 15% of all sequenced bacterial and archaeal genomes, but the molecular basis of how Gabija defends cells from viral infection remains poorly understood. Here we use X-ray crystallography and cryo-electron microscopy (cryo-EM) to define how Gabija proteins assemble into a supramolecular complex of around 500 kDa that degrades phage DNA. Gabija protein A (GajA) is a DNA endonuclease that tetramerizes to form the core of the anti-phage defence complex. Two sets of Gabija protein B (GajB) dimers dock at opposite sides of the complex and create a 4:4 GajA-GajB assembly (hereafter, GajAB) that is essential for phage resistance in vivo. We show that a phage-encoded protein, Gabija anti-defence 1 (Gad1), directly binds to the Gabija GajAB complex and inactivates defence. A cryo-EM structure of the virally inhibited state shows that Gad1 forms an octameric web that encases the GajAB complex and inhibits DNA recognition and cleavage. Our results reveal the structural basis of assembly of the Gabija anti-phage defence complex and define a unique mechanism of viral immune evasion.
Topics: Bacteria; Bacterial Proteins; Bacteriophages; Cryoelectron Microscopy; Crystallography, X-Ray; Deoxyribonucleases; DNA, Viral; Immune Evasion; Protein Multimerization
PubMed: 37992757
DOI: 10.1038/s41586-023-06855-2