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1.
J Eur Acad Dermatol Venereol ; 36(8): 1342-1348, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1807161

ABSTRACT

BACKGROUND: Reactivation of the varicella-zoster virus (VZV), which causes herpes zoster (HZ, synonym: shingles) in humans, can be a rare adverse reaction to vaccines. Recently, reports of cases after COVID-19 vaccination have arisen. OBJECTIVES: The aim of this study was to assess whether the frequency of HZ is found to increase after COVID-19 vaccination in a large cohort, based on real-world data. As a hypothesis, the incidence of HZ was assumed to be significantly higher in subjects who received a COVID-19 vaccine (Cohort I) vs. unvaccinated individuals (Cohort II). METHODS: The initial cohorts of 1 095 086 vaccinated and 16 966 018 unvaccinated patients were retrieved from the TriNetX database and were matched on age and gender in order to mitigate confounder bias. RESULTS: After matching, each cohort accounted for 1 095 086 patients. For the vaccinated group (Cohort I), 2204 subjects developed HZ within 60 days of COVID-19 vaccination, while among Cohort II, 1223 patients were diagnosed with HZ within 60 days after having visited the clinic for any other reason (i.e. not vaccination). The risk of developing shingles was calculated as 0.20% and 0.11% for cohort I and cohort II, respectively. The difference was statistically highly significant (P < 0.0001; log-rank test). The risk ratio and odds ratio were 1.802 (95% confidence interval [CI] = 1.680; 1.932) and 1.804 (95% CI = 1.682; 1.934). CONCLUSIONS: Consistent with the hypothesis, a higher incidence of HZ was statistically detectable post-COVID-19 vaccine. Accordingly, the eruption of HZ may be a rare adverse drug reaction to COVID-19 vaccines. Even though the molecular basis of VZV reactivation remains murky, temporary compromising of VZV-specific T-cell-mediated immunity may play a mechanistic role in post-vaccination pathogenesis of HZ. Note that VZV reactivation is a well-established phenomenon both with infections and with other vaccines (i.e. this adverse event is not COVID-19-specific).


Subject(s)
COVID-19 Vaccines , COVID-19 , Herpes Zoster , Herpesvirus 3, Human , Virus Activation , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Herpes Zoster/epidemiology , Herpes Zoster/etiology , Herpesvirus 3, Human/physiology , Humans , Vaccination/adverse effects
2.
Hepatol Int ; 16(2): 257-268, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1797505

ABSTRACT

The world has made significant progress in developing novel treatments for COVID-19 since the pandemic began. Some treatments target the patient's dysregulated inflammatory response during COVID-19 infection and may cause hepatitis B reactivation (HBVr) in patients with current or past hepatitis B virus (HBV) infection. This review summarizes the risk and management of HBVr due to different treatments of COVID-19 in patients who have current or past HBV infection. Abnormal liver function tests are common during COVID-19 infection. Current evidence suggests that current or past HBV infection is not associated with an increased risk of liver injury and severe disease in COVID-19 patients. Among patients who received high-dose corticosteroids, various immunosuppressive monoclonal antibodies and inhibitors of Janus kinase, the risk of HBVr exists, especially among those without antiviral prophylaxis. Data, however, remain scarce regarding the specific use of immunosuppressive therapies in COVID-19 patients with HBV infection. Some results are mainly extrapolated from patients receiving the same agents in other diseases. HBVr is a potentially life-threatening event following profound immunosuppression by COVID-19 therapies. Future studies should explore the use of immunosuppressive therapies in COVID-19 patients with HBV infection and the impact of antiviral prophylaxis on the risk of HBVr.


Subject(s)
COVID-19 , Hepatitis B , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Hepatitis B/prevention & control , Hepatitis B Surface Antigens , Hepatitis B virus , Humans , Immunosuppressive Agents/adverse effects , Virus Activation/physiology
4.
Antimicrob Agents Chemother ; 66(3): e0239521, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1741569

ABSTRACT

Recently, remdesivir and molnupiravir were approved for treating COVID-19 caused by SARS-CoV-2 infection. However, little is known about the impact of these drugs on other viruses preexisted in COVID-19 patients. Here we report that remdesivir but not molnupiravir induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), two major oncogenic herpesviruses. Remdesivir induced mature virion production from latently infected cells. Mechanistic studies showed that remdesivir induced KSHV and EBV reactivation by regulating several intracellular signaling pathways.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Herpesvirus 8, Human , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Herpesvirus 4, Human/physiology , Humans , SARS-CoV-2 , Signal Transduction , Virus Activation
5.
Front Immunol ; 12: 797390, 2021.
Article in English | MEDLINE | ID: covidwho-1686476

ABSTRACT

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to ß-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and ß-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells , Phosphodiesterase 4 Inhibitors/pharmacology , RNA/pharmacology , SARS-CoV-2/physiology , Virus Activation/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Cytokines/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , Humans , Th1 Cells/immunology , Th2 Cells/immunology , Virus Activation/immunology
6.
Front Immunol ; 12: 784145, 2021.
Article in English | MEDLINE | ID: covidwho-1674332

ABSTRACT

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for vaccines to protect individuals at high risk for complications and to potentially control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge about adverse events of SARS-CoV-2 vaccines during post-marketing surveillance. Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation has already been reported in COVID-19 patients. In addition, adverse events after SARS-CoV-2 mRNA vaccination have also been in the context of varicella zoster virus (VZV) reactivation and directly associated with the mRNA vaccine. We present the first case of CMV reactivation and pericarditis in temporal association with SARS-CoV-2 vaccination, particularly adenovirus-based DNA vector vaccine ChAdOx1 nCoV-19 against SARS-CoV-2. After initiation of antiviral therapy with oral valganciclovir, CMV viremia disappeared and clinical symptoms rapidly improved. Since huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must be in place to assess vaccine safety that is important for the detection of any events. In the context of the hundreds of millions of individuals to be vaccinated against SARS-CoV-2, a potential causal association with CMV reactivation may result in a considerable number of cases with potentially severe complications.


Subject(s)
/adverse effects , Cytomegalovirus/drug effects , Pericarditis/chemically induced , SARS-CoV-2/immunology , Virus Activation/drug effects , Aged , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Cytomegalovirus/physiology , Cytomegalovirus Infections/chemically induced , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Female , Humans , Pericarditis/drug therapy , Pericarditis/virology , Treatment Outcome , Valganciclovir/therapeutic use , Viremia/chemically induced , Viremia/drug therapy , Viremia/virology
7.
AIDS Rev ; 23(3): 153-163, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1579385

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious RNA coronavirus responsible for the pandemic of the coronavirus disease 2019 (COVID-19). Recent advances in virology, epidemiology, diagnosis, and clinical management of COVID-19 have contributed to the control and prevention of this disease, but re-positivity of SARS-CoV-2 in recovered COVID-19 patients has brought a new challenge for this worldwide anti-viral battle. Reverse transcription polymerase chain reaction (RT-PCR) tests of the SARS-CoV-2 pathogen is widely used in clinical diagnosis, but a positive RT-PCR result may be multifactorial, including false positive, SARS-CoV-2 RNA fragment shedding, reinfection of SARS-CoV-2, or re-activation of COVID-19. Re-infection of SARS-CoV-2 or re-activation of COVID-19 is an indicator of live viral carriers and isolation/treatment is needed, but SARS-CoV-2 RNA fragment shedding is not. SARS-CoV-2 RNA is recently reported to integrate into the host genome, but the far-reaching outcome is currently unclear. Therefore, it is critical for appropriate manipulation and prevention of COVID-19 to distinguish these causal factors of SARS-CoV-2 re-positivity. In this review article, we updated the current knowledge of SARS-CoV-2 re-positivity in discharged COVID-19 patients with a focus on re-infection and re-activation. We proposed a hypothetical flowchart for handling of the SARS-CoV-2 re-positive cases.


Subject(s)
COVID-19/pathology , RNA, Viral/analysis , Reinfection/virology , SARS-CoV-2/genetics , Virus Activation/genetics , Adaptive Immunity/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/diagnosis , Child , Child, Preschool , False Positive Reactions , Female , Humans , Infant , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Young Adult
8.
Cell Rep ; 37(13): 110144, 2021 12 28.
Article in English | MEDLINE | ID: covidwho-1588144

ABSTRACT

Kaposi's sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensing machinery is central to its oncogenicity. By upregulating the hypoxia-inducible factors (HIFs), KSHV reprograms infected cells to a hypoxia-like state, triggering angiogenesis. Here we identify a link between KSHV replicative biology and oncogenicity by showing that KSHV's ability to regulate HIF2α levels and localization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs through the HIF2α-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cells is critical for lytic protein synthesis and contributes to KSHV-induced PDGFRA activation and VEGF secretion. Thus, KSHV regulation of the oxygen-sensing machinery allows virally infected cells to initiate translation via the mTOR-dependent eIF4E1 or the HIF2α-dependent, mTOR-independent, eIF4E2. This "translation initiation plasticity" (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinogenesis/pathology , Herpesvirus 8, Human/physiology , Hypoxia/physiopathology , Peptide Chain Initiation, Translational , Sarcoma, Kaposi/pathology , Virus Replication , Basic Helix-Loop-Helix Transcription Factors/genetics , Carcinogenesis/genetics , Carcinogenesis/metabolism , Eukaryotic Initiation Factor-4E/genetics , Eukaryotic Initiation Factor-4E/metabolism , Humans , Sarcoma, Kaposi/genetics , Sarcoma, Kaposi/metabolism , Sarcoma, Kaposi/virology , Virus Activation
10.
Heart Surg Forum ; 24(6): E940-E946, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1538255

ABSTRACT

BACKGROUND: The aim of this study was to investigate the clinical outcomes of cardiac surgery in patients who were incidentally diagnosed with Covid-19 in the postoperative period. PATIENTS AND METHODS: We performed 826 open cardiac surgeries in five tertiary centers. Most of the surgeries were elective coronary artery bypass grafting (CABG) (93.8%). A preoperative RT-PCR test and transcutaneous oxygen saturation were routinely investigated prior to surgery. We also investigated whether the patients already received Covid-19 treatment or had any contact with a Covid-19 patient in the last two weeks. We analyzed high sensitive C-reactive protein (hs-CRP), d-dimer, and fibrinogen, which plays a main role in the activation of procoagulant state after surgeries. RESULTS: Acute lung injury related to Covid-19 activation was observed in 48 out of 826 patients (5.8%). The median age of 48 patients was 63.9±12.4 years. Euro-Score and body mass index (BMI) were 6.1±1.1 and 29.2±4.1kg/m², respectively. RT-PCR test results were positive in 29 patients (60.4%). We performed thoracic computed tomography (CT) in all patients with or without positive RT-PCR test results. Thoracic CT images showed that there was a different degree of ARDS (mild, moderate, and serious). The median time of extracorporeal circulation (ECC) was 93.2±14.6 min. in on-pump surgery (IQR, 68-155 min.). Common symptoms included dyspnea (N = 22; 45.8%) and fever (N = 12; 25%). Eleven patients needed readmission to ICU. Compared with non-admitted to ICU patients, ICU patients were higher comorbidities and severe laboratory abnormalities (eg, high blood d-dimer and fibrinogen). We also detected significantly low oxygen saturation, hypercapnia, and severe acidosis in readmitted patients. Radiologic investigations showed that there were severe ARDS with bilateral pneumonic infiltration resistant to medical treatment in 6 out of 11 patients who died (54.5%). CONCLUSION: Diffuse pneumonic infiltration related to Covid-19 may develop in asymptomatic cardiac surgery patients with negative RT-PCR test results. Immunologic disorders resulting from ECC, physiologic distress, and anesthesia may activate Covid-19 during the incubation period. We need randomized clinical trials to explain Covid-19 activation in the latent period of the virus, and clinical outcomes in cardiac surgery.


Subject(s)
Acute Lung Injury/diagnosis , Acute Lung Injury/virology , COVID-19/diagnosis , COVID-19/virology , Cardiac Surgical Procedures , Postoperative Period , Acute Lung Injury/diagnostic imaging , Aged , COVID-19/diagnostic imaging , COVID-19 Nucleic Acid Testing , Critical Care , Female , Humans , Incidental Findings , Male , Middle Aged , Patient Readmission , Retrospective Studies , SARS-CoV-2 , Stress, Physiological , Tomography, X-Ray Computed , Virus Activation
11.
J Virol ; 95(13): e0019221, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1486499

ABSTRACT

Understanding factors that affect the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is central to combatting coronavirus disease 2019 (COVID-19). The virus surface spike protein of SARS-CoV-2 mediates viral entry into cells by binding to the ACE2 receptor on epithelial cells and promoting fusion. We found that Epstein-Barr virus (EBV) induces ACE2 expression when it enters the lytic replicative cycle in epithelial cells. By using vesicular stomatitis virus (VSV) particles pseudotyped with the SARS-CoV-2 spike protein, we showed that lytic EBV replication enhances ACE2-dependent SARS-CoV-2 pseudovirus entry. We found that the ACE2 promoter contains response elements for Zta, an EBV transcriptional activator that is essential for EBV entry into the lytic cycle of replication. Zta preferentially acts on methylated promoters, allowing it to reactivate epigenetically silenced EBV promoters from latency. By using promoter assays, we showed that Zta directly activates methylated ACE2 promoters. Infection of normal oral keratinocytes with EBV leads to lytic replication in some of the infected cells, induces ACE2 expression, and enhances SARS-CoV-2 pseudovirus entry. These data suggest that subclinical EBV replication and lytic gene expression in epithelial cells, which is ubiquitous in the human population, may enhance the efficiency and extent of SARS-CoV-2 infection of epithelial cells by transcriptionally activating ACE2 and increasing its cell surface expression. IMPORTANCE SARS-CoV-2, the coronavirus responsible for COVID-19, has caused a pandemic leading to millions of infections and deaths worldwide. Identifying the factors governing susceptibility to SARS-CoV-2 is important in order to develop strategies to prevent SARS-CoV-2 infection. We show that Epstein-Barr virus, which infects and persists in >90% of adult humans, increases susceptibility of epithelial cells to infection by SARS-CoV-2. EBV, when it reactivates from latency or infects epithelial cells, increases expression of ACE2, the cellular receptor for SARS-CoV-2, enhancing infection by SARS-CoV-2. Inhibiting EBV replication with antivirals may therefore decrease susceptibility to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Epithelial Cells/virology , Herpesvirus 4, Human/physiology , SARS-CoV-2/physiology , Virus Internalization , Virus Replication , Angiotensin-Converting Enzyme 2/metabolism , Cell Line , DNA Methylation , Epithelial Cells/metabolism , Gene Expression Regulation , Humans , Promoter Regions, Genetic , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Trans-Activators/metabolism , Virus Activation
12.
Gastroenterol Hepatol ; 45(4): 256-264, 2022 Apr.
Article in English, Spanish | MEDLINE | ID: covidwho-1450112

ABSTRACT

AIMS: To evaluate the results of a hepatitis B and C screening program in hospitalized COVID-19 patients. METHOD: Transversal prospective study conducted in two Spanish hospitals. Patients admitted from March 1st to December 31st 2020 with a diagnosis of COVID-19 were tested for markers of hepatitis B (HBsAg, anti-HBc) and C (anti-HCV, HCV RNA) infection. RESULTS: In this period, 4662 patients with COVID-19 were admitted to our centers: 56.3% were male, median age was 76 (0-104) years. Data regarding HBV infection was available in 2915 (62.5%) patients; 253 (8.75%) were anti-HBc+ and 11 (0.38%) HBsAg+. From these, 4 patients did not have a previous diagnosis of hepatitis B, 7 received corticosteroids and one received prophylaxis. There was one HBV reactivation. Anti-HCV was available in 2895 (62%) patients; 24 (0.83%) were positive. From these, 13 patients had a previous hepatitis C diagnosis: 10 patients had been treated with SVR, one achieved spontaneous cure and 2 did not receive treatment. From the 11 previously unknown anti-VHC+patients, 10 had a negative HCV RNA. Overall, only 3 (0.10%) patients tested RNA HCV+. However, none received HCV treatment (2 older than 90 years with comorbidities, 1 died from COVID-19). CONCLUSION: Screening of hepatitis C infection in hospitalized COVID-19 patients seems less useful than expected. The low prevalence of active infection after antiviral treatments and the high age of our population limit the detection of potential candidates for treatment. HBV screening should be aimed to prevent reactivation under immunosuppressive treatments.


Subject(s)
COVID-19 , Hepatitis B , Hepatitis C , Aged , Hepatitis B/diagnosis , Hepatitis B/epidemiology , Hepatitis B/prevention & control , Hepatitis B Antibodies , Hepatitis B Surface Antigens , Hepatitis B virus , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Humans , Male , Prospective Studies , SARS-CoV-2 , Virus Activation
13.
BMC Infect Dis ; 21(1): 955, 2021 Sep 15.
Article in English | MEDLINE | ID: covidwho-1414111

ABSTRACT

BACKGROUND: Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. METHOD: This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. RESULTS: Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. CONCLUSIONS: In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.


Subject(s)
COVID-19 , Epstein-Barr Virus Infections , Critical Illness , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/epidemiology , Herpesvirus 4, Human , Humans , Retrospective Studies , SARS-CoV-2 , Virus Activation
14.
PLoS Pathog ; 17(9): e1009898, 2021 09.
Article in English | MEDLINE | ID: covidwho-1394564

ABSTRACT

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 µM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Ethacridine/pharmacology , Protease Inhibitors/pharmacology , Virus Activation/drug effects , Animals , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Genes, Reporter , Green Fluorescent Proteins/genetics , Humans , Vero Cells , Virion/drug effects , Virus Replication/drug effects
15.
Epidemiol Infect ; 149: e145, 2021 06 16.
Article in English | MEDLINE | ID: covidwho-1392726

ABSTRACT

The appearance on the skin of herpes virus lesions, concomitantly with the coronavirus disease 2019 (COVID-19) pandemic, leads us to suspect an underlying infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Diagnostic reverse transcriptase polymerase chain reaction tests and immunoglobulin M (IgM) and IgG seroconversion studies have therefore been carried out. We present three cases of herpes virus infections in immunocompetent patients: one of the infections was herpes simplex 1 in a 40-year-old woman, and the other two were herpes varicella-zoster infections in a 62-year-old man and a 25-year-old woman. The patients were in the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. The SARS-CoV-2 infection was confirmed in only one of the three cases. In this study, we briefly review the etiopathogenic role of the COVID-19 pandemic situation, whereby immunodeficiencies are generated that favour the appearance of other viral infections, such as herpes virus infections.


Subject(s)
COVID-19/complications , Herpes Simplex/etiology , Herpes Zoster/etiology , Herpesvirus 3, Human/physiology , Simplexvirus/physiology , Virus Activation , Adult , COVID-19/epidemiology , COVID-19/virology , Female , Herpes Simplex/diagnosis , Herpes Simplex/virology , Herpes Zoster/diagnosis , Herpes Zoster/virology , Humans , Male , Middle Aged , Risk Factors , Spain/epidemiology
16.
Nat Commun ; 12(1): 5000, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361637

ABSTRACT

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.


Subject(s)
Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/drug effects , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Epitopes , Female , HEK293 Cells , Haplorhini , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Pandemics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Vero Cells , Virus Activation
17.
EMBO Mol Med ; 13(8): e13901, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1346766

ABSTRACT

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+ /NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a "shock and kill effect" decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.


Subject(s)
HIV Infections , HIV-1 , CD4-Positive T-Lymphocytes , Down-Regulation , Glycolysis , Humans , Oxidative Stress , Proteomics , Virus Activation , Virus Latency
18.
Int J Antimicrob Agents ; 58(4): 106409, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330851

ABSTRACT

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of antimicrobial resistance. While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and intensive care units (ICUs), an increase in empirical antibiotic use has been described. In the ICU setting, where antibiotics are already abundantly-and often inappropriately-prescribed, the need for an ICU-specific antimicrobial stewardship programme is widely advocated. Apart from essentially warning against the use of antibacterial drugs for the treatment of a viral infection, other aspects of ICU antimicrobial stewardship need to be considered in view of the clinical course and characteristics of COVID-19. First, the distinction between infectious and non-infectious (inflammatory) causes of respiratory deterioration during an ICU stay is difficult, and the much-debated relevance of fungal and viral co-infections adds to the complexity of empirical antimicrobial prescribing. Biomarkers such as procalcitonin for the decision to start antibacterial therapy for ICU nosocomial infections seem to be more promising in COVID-19 than non-COVID-19 patients. In COVID-19 patients, cytomegalovirus reactivation is an important factor to consider when assessing patients infected with SARS-CoV-2 as it may have a role in modulating the patient immune response. The diagnosis of COVID-19-associated invasive aspergillosis is challenging because of the lack of sensitivity and specificity of the available tests. Furthermore, altered pharmacokinetic/pharmacodynamic properties need to be taken into account when prescribing antimicrobial therapy. Future research should now further explore the 'known unknowns', ideally with robust prospective study designs.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antimicrobial Stewardship/methods , COVID-19 , Cross Infection/diagnosis , Anti-Bacterial Agents/pharmacokinetics , Antimicrobial Stewardship/organization & administration , Biomarkers/analysis , COVID-19/drug therapy , Coinfection/drug therapy , Coinfection/microbiology , Cross Infection/drug therapy , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Humans , Intensive Care Units , Invasive Pulmonary Aspergillosis/diagnosis , Invasive Pulmonary Aspergillosis/drug therapy , Virus Activation/drug effects
19.
PLoS One ; 16(7): e0254129, 2021.
Article in English | MEDLINE | ID: covidwho-1291694

ABSTRACT

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases ("early" phase 1: day 1-10, "middle" phase 2: day 11-30 and "late" phase 3: day 31-40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.


Subject(s)
COVID-19/therapy , Herpes Simplex/etiology , Herpesvirus 1, Human/physiology , Respiration, Artificial , Virus Activation , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/immunology , Female , Herpes Simplex/immunology , Herpesvirus 1, Human/immunology , Herpesvirus 1, Human/isolation & purification , Humans , Immunity, Innate , Male , Middle Aged , Respiration, Artificial/adverse effects , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
20.
Commun Biol ; 4(1): 682, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1260957

ABSTRACT

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/complications , Herpesvirus 8, Human/physiology , SARS-CoV-2/physiology , Sarcoma, Kaposi/etiology , Virus Activation , Azithromycin/pharmacology , Benzamidines/pharmacology , COVID-19/drug therapy , Cell Line , Guanidines/pharmacology , Herpesviridae Infections/chemically induced , Herpesviridae Infections/etiology , Herpesvirus 8, Human/drug effects , Humans , Oncogenic Viruses/drug effects , Oncogenic Viruses/physiology , SARS-CoV-2/drug effects , Sarcoma, Kaposi/chemically induced , Viral Proteins/metabolism , Virus Activation/drug effects
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