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Expert Review of Respiratory Medicine Aug 2021Therapy of coronavirus disease 2019 (COVID-19) involves evolving algorithms that include drugs aimed at reducing disease progression by counteracting two different, but...
INTRODUCTION
Therapy of coronavirus disease 2019 (COVID-19) involves evolving algorithms that include drugs aimed at reducing disease progression by counteracting two different, but intertwined processes: () the damage caused by the virus (with antivirals); () the damage caused by a dysregulated host response (with immunomodulatory agents).
AREAS COVERED
Herein, we discuss the available evidence on the efficacy and safety of antiviral agents employed over the past months for the treatment of COVID-19, and the reasons to be considered for antiviral selection.
EXPERT OPINION
The available evidence from randomized controlled trials (RCT) currently discourages the use of lopinavir/ritonavir, hydroxychloroquine, and interferons, which did not show improved efficacy compared to standard care or placebo. Regarding remdesivir, the current body of evidence may conditionally support its use in COVID-19 patients requiring oxygen supplementation but still not requiring invasive mechanical ventilation. Finally, neutralizing monoclonal antibodies have been proven efficacious in reducing the risk of severe disease development if administered early in the course of the disease to patients at risk of progression. The results of the ongoing RCT will certainly be crucial to further improve our understanding of the optimal place in therapy of antiviral agents for COVID-19.
Topics: Antiviral Agents; COVID-19; Humans; Hydroxychloroquine; Lopinavir; SARS-CoV-2; Treatment Outcome
PubMed: 33962524
DOI: 10.1080/17476348.2021.1927719 -
Journal of Medical Virology Nov 2023The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and...
The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma-derived HBV (genotype B and C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, covalently closed circular DNA [cccDNA], extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes [ISG]) to interferon-α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor-dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor-dependent drug responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor-dependent variation in viral dynamics and cellular responses. These features can be utilized for the development of personalized drug testing platform for antivirals.
Topics: Humans; Hepatitis B virus; Hepatitis B Surface Antigens; Hepatitis B e Antigens; Hepatitis B, Chronic; Hepatitis B; Interferon-alpha; DNA, Circular; Antiviral Agents; Organoids; RNA; DNA, Viral; Liver
PubMed: 38009279
DOI: 10.1002/jmv.29232 -
Infectious Disorders Drug Targets 2020Viral interference, originally, referred to a state of temporary immunity, is a state whereby infection with a virus limits replication or production of a second... (Review)
Review
Viral interference, originally, referred to a state of temporary immunity, is a state whereby infection with a virus limits replication or production of a second infecting virus. However, replication of a second virus could also be dominant over the first virus. In fact, dominance can alternate between the two viruses. Expression of type I interferon genes is many times upregulated in infected epithelial cells. Since the interferon system can control most, if not all, virus infections in the absence of adaptive immunity, it was proposed that viral induction of a nonspecific localized temporary state of immunity may provide a strategy to control viral infections. Clinical observations also support such a theory, which gave credence to the development of superinfection therapy (SIT). SIT is an innovative therapeutic approach where a non-pathogenic virus is used to infect patients harboring a pathogenic virus. For the functional cure of persistent viral infections and for the development of broad- spectrum antivirals against emerging viruses a paradigm shift was recently proposed. Instead of the virus, the therapy should be directed at the host. Such a host-directed-therapy (HDT) strategy could be the activation of endogenous innate immune response via toll-like receptors (TLRs). Superinfection therapy is such a host-directed-therapy, which has been validated in patients infected with two completely different viruses, the hepatitis B (DNA), and hepatitis C (RNA) viruses. SIT exerts post-infection interference via the constant presence of an attenuated non-pathogenic avian double- stranded (ds) RNA viral vector which boosts the endogenous innate (IFN) response. SIT could, therefore, be developed into a biological platform for a new "one drug, multiple bugs" broad-spectrum antiviral treatment approach.
Topics: Animals; Antiviral Agents; Gene Expression; Humans; Immunity, Innate; Interferon Type I; RNA Viruses; Viral Interference; Viral Load; Virus Replication
PubMed: 30950360
DOI: 10.2174/1871526519666190405140858 -
Frontiers in Immunology 2023After recognition of cognate antigen (Ag), effector CD8 T cells secrete serine proteases called granzymes in conjunction with perforin, allowing granzymes to enter and...
After recognition of cognate antigen (Ag), effector CD8 T cells secrete serine proteases called granzymes in conjunction with perforin, allowing granzymes to enter and kill target cells. While the roles for some granzymes during antiviral immune responses are well characterized, the function of others, such as granzyme C and its human ortholog granzyme H, is still unclear. Granzyme C is constitutively expressed by mature, cytolytic innate lymphoid 1 cells (ILC1s). Whether other antiviral effector cells also produce granzyme C and whether it is continually expressed or responsive to the environment is unknown. To explore this, we analyzed granzyme C expression in different murine skin-resident antiviral lymphocytes. At steady-state, dendritic epidermal T cells (DETCs) expressed granzyme C while dermal γδ T cells did not. CD8 tissue-resident memory T cells (T) generated in response to cutaneous viral infection with the poxvirus vaccinia virus (VACV) also expressed granzyme C. Both DETCs and virus-specific CD8 T upregulated granzyme C upon local VACV infection. Continual Ag exposure was not required for maintained T expression of granzyme C, although re-encounter with cognate Ag boosted expression. Additionally, IL-15 treatment increased granzyme C expression in both DETCs and T. Together, our data demonstrate that granzyme C is widely expressed by antiviral T cells in the skin and that expression is responsive to both environmental stimuli and TCR engagement. These data suggest that granzyme C may have functions other than killing in tissue-resident lymphocytes.
Topics: Mice; Humans; Animals; Granzymes; CD8-Positive T-Lymphocytes; Antiviral Agents; Immunity, Innate; Lymphocytes; Antigens; Vaccinia virus
PubMed: 37809077
DOI: 10.3389/fimmu.2023.1236595 -
Emerging Microbes & Infections Jan 2016Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and... (Review)
Review
Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry.
Topics: Antiviral Agents; Drug Discovery; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Humans; Interferon-alpha; Liver Neoplasms; Liver Transplantation; Virus Internalization
PubMed: 26733381
DOI: 10.1038/emi.2016.3 -
Viruses May 2022Immune homeostasis is achieved by balancing the activating and inhibitory signal transduction pathways mediated via cell surface receptors. Activation allows the host to... (Review)
Review
Immune homeostasis is achieved by balancing the activating and inhibitory signal transduction pathways mediated via cell surface receptors. Activation allows the host to mount an immune response to endogenous and exogenous antigens; suppressive modulation via inhibitory signaling protects the host from excessive inflammatory damage. The checkpoint regulation of myeloid cells during immune homeostasis raised their profile as important cellular targets for treating allergy, cancer and infectious disease. This review focuses on the structure and signaling of inhibitory receptors on myeloid cells, with particular attention placed on how the interplay between viruses and these receptors regulates antiviral immunity. The status of targeting inhibitory receptors on myeloid cells as a new therapeutic approach for antiviral treatment will be analyzed.
Topics: Antiviral Agents; Humans; Myeloid Cells; Neoplasms; Signal Transduction
PubMed: 35746616
DOI: 10.3390/v14061144 -
Advances in Experimental Medicine and... 2021Emerging and re-emerging viral diseases occur with regularity within the human population. The conventional 'one drug, one virus' paradigm for antivirals does not...
Emerging and re-emerging viral diseases occur with regularity within the human population. The conventional 'one drug, one virus' paradigm for antivirals does not adequately allow for proper preparedness in the face of unknown future epidemics. In addition, drug developers lack the financial incentives to work on antiviral drug discovery, with most pharmaceutical companies choosing to focus on more profitable disease areas. Safe-in-man broad spectrum antiviral agents (BSAAs) can help meet the need for antiviral development by already having passed phase I clinical trials, requiring less time and money to develop, and having the capacity to work against many viruses, allowing for a speedy response when unforeseen epidemics arise. In this chapter, we discuss the benefits of repurposing existing drugs as BSAAs, describe the major steps in safe-in-man BSAA drug development from discovery through clinical trials, and list several database resources that are useful tools for antiviral drug repositioning.
Topics: Antiviral Agents; Drug Discovery; Drug Repositioning; Humans; Virus Diseases; Viruses
PubMed: 34258746
DOI: 10.1007/978-981-16-0267-2_12 -
Trends in Immunology Jan 2021The majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals remain paucisymptomatic, contrasting with a minority of infected... (Review)
Review
The majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals remain paucisymptomatic, contrasting with a minority of infected individuals in danger of death. Here, we speculate that the robust disease resistance of most individuals is due to a swift production of type I interferon (IFNα/β), presumably sufficient to lower the viremia. A minority of infected individuals with a preexisting chronic inflammatory state fail to mount this early efficient response, leading to a delayed harmful inflammatory response. To improve the epidemiological scenario, we propose combining: (i) the development of efficient antivirals administered early enough to assist in the production of endogenous IFNα/β; (ii) potentiating early IFN responses; (iii) administering anti-inflammatory treatments when needed, but not too early to interfere with endogenous antiviral responses.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Cytokines; Humans; Immunologic Factors; Interferon Type I; SARS-CoV-2; Serine Endopeptidases; Virus Replication; COVID-19 Drug Treatment
PubMed: 33281063
DOI: 10.1016/j.it.2020.11.003 -
Drug Design, Development and Therapy 2022The aim of this report is to review the literature and shed light on the uncertainties surrounding the use of antiviral agents in general and remdesivir in COVID-19... (Review)
Review
The aim of this report is to review the literature and shed light on the uncertainties surrounding the use of antiviral agents in general and remdesivir in COVID-19 patients. This review evaluated a battery of antiviral compounds and their effectiveness in the treatment of COVID-19 since the beginning of the pandemic. Remdesivir is the only antiviral approved by the EMA and FDA for the treatment of SARS-CoV-2 infection. This work extensively reviews remdesivir data generated from clinical trials and observational studies, paying attention to the most recent data, and focusing on outcomes to give readers a more comprehensive understanding of the results. This review also discusses the recommendations issued by official bodies during the pandemic in the light of the current knowledge. The use of remdesivir in the treatment of SARS-CoV-2 infection is justified because a virus is the causative agent that triggers the inflammatory responses and its consequences. More trials are needed to improve the management of this disease.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 35370401
DOI: 10.2147/DDDT.S356951 -
Advances in Experimental Medicine and... 2018Dengue is the most important mosquito-borne viral disease in the world, representing a major unmet medical need and a growing public health concern. The disease imposes... (Review)
Review
Dengue is the most important mosquito-borne viral disease in the world, representing a major unmet medical need and a growing public health concern. The disease imposes a heavy burden to the affected individuals, to the health care systems, and to the economies of endemic countries. Vector control is the most widespread tool to curb dengue epidemics, but has been insufficient. Therefore, additional means such as vaccines and antivirals are required to aid in a coordinated response. The discovery and development of small molecule dengue virus inhibitors as a tool to prevent and/or treat dengue disease faces major hurdles in combining pan-serotypic efficacy, safety, and optimal drug-like properties. Moreover, the financial return of dengue drug projects may not compensate for the initial investment in research and development. This review article addresses the efforts undertaken to face the dengue epidemics, focusing on antiviral drug development. The dengue drug research and development process is described in detail and a dengue antiviral target product profile is proposed. The article discusses collaborations between the different players in the research field: government and government-sponsored organizations, pharmaceutical and biotechnology companies, academia, and non-profit and philanthropic organizations. Public-private partnerships are proposed as a model to boost dengue research and development towards an approved antiviral drug in the near future.
Topics: Animals; Antiviral Agents; Dengue; Dengue Virus; Drug Discovery; Drug Industry; History, 20th Century; History, 21st Century; Humans; Research
PubMed: 29845543
DOI: 10.1007/978-981-10-8727-1_23