Effect of Cytomegalovirus Reactivation on Inflammatory Status and Mortality of Older COVID-19 Patients.

Herpesviridae reactivation such as cytomegalovirus (CMV) has been described in severe COVID-19 (COronaVIrusDisease-2019). This study aimed to understand if CMV reactivation in older COVID-19 patients is associated with increased inflammation and in-hospital mortality. In an observational single-center cohort study, 156 geriatric COVID-19 patients were screened for CMV reactivation by RT-PCR. Participants underwent a comprehensive clinical investigation that included medical history, functional evaluation, laboratory tests and cytokine assays (TNF-α, IFN-α, IL-6, IL-10) at hospital admission. In 19 (12.2%) of 156 COVID-19 patients, CMV reactivation was detected. Multivariate Cox regression models showed that in-hospital mortality significantly increased among CMV positive patients younger than 87 years (HR: 9.94, 95% CI: 1.66-59.50). Other factors associated with in-hospital mortality were C-reactive protein (HR: 1.17, 95% CI: 1.05-1.30), neutrophil count (HR: 1.20, 95% CI: 1.01-1.42) and clinical frailty scale (HR:1.54, 95% CI: 1.04-2.28). In patients older than 87 years, neutrophil count (HR: 1.13, 95% CI: 1.05-1.21) and age (HR: 1.15, 95% CI: 1.01-1.31) were independently associated with in-hospital mortality. CMV reactivation was also correlated with increased IFN-α and TNF-α serum levels, but not with IL-6 and IL-10 serum changes. In conclusion, CMV reactivation was an independent risk factor for in-hospital mortality in COVID-19 patients younger than 87 years old, but not in nonagenarians.

COVID-19 infection and vaccines: potential triggers of Herpesviridae reactivation.

Since the onset of the COVID-19 outbreak, numerous articles have highlighted a possible link between COVID-19 vaccination or infection and Herpesviridae co-infection or reactivation. The authors conducted an exhaustive literature review on this topic, the results of which are presented individually for each member of the Herpesviridae family: Herpes Simplex Virus (HSV) types-1 (HSV-1) and 2 (HSV-2); Varicella-Zoster Virus (VZV); Epstein-Barr Virus (EBV); Cytomegalovirus (CMV); HHV-6; HHV-7; and HHV-8. These human herpesviruses can serve as prognostic markers for the COVID-19 infection and may even underlie some of the clinical manifestations initially attributed to SARS-CoV-2. In addition to SARS-CoV-2 infection, all corresponding vaccines approved to date in Europe appear capable of inducing herpesvirus reactivation. It is important to consider all viruses of the Herpesviridae family when managing patients infected with or recently vaccinated against COVID-19.

Efficacy Validation of SARS-CoV-2-Inactivation and Viral Genome Stability in Saliva by a Guanidine Hydrochloride and Surfactant-Based Virus Lysis/Transport Buffer.

To enhance biosafety and reliability in SARS-CoV-2 molecular diagnosis, virus lysis/transport buffers should inactivate the virus and preserve viral RNA under various conditions. Herein, we evaluated the SARS-CoV-2-inactivating activity of guanidine hydrochloride (GuHCl)- and surfactant (hexadecyltrimethylammonium chloride (Hexa-DTMC))-based buffer, Prep Buffer A, (Precision System Science Co., Ltd., Matsudo, Japan) and its efficacy in maintaining the stability of viral RNA at different temperatures using the traditional real-time one-step RT-PCR and geneLEAD VIII sample-to-result platform. Although Prep Buffer A successfully inactivated SARS-CoV-2 in solutions with high and low organic substance loading, there was considerable viral genome degradation at 35 °C compared with that at 4 °C. The individual roles of GuHCl and Hexa-DTMC in virus inactivation and virus genome stability at 35 °C were clarified. Hexa-DTMC alone (0.384%), but not 1.5 M GuHCl alone, exhibited considerable virucidal activity, suggesting that it was essential for potently inactivating SARS-CoV-2 using Prep Buffer A. GuHCl and Hexa-DTMC individually reduced the viral copy numbers to the same degree as Prep Buffer A. Although both components inhibited RNase activity, Hexa-DTMC, but not GuHCl, directly destroyed naked viral RNA. Our findings suggest that samples collected in Prep Buffer A should be stored at 4 °C when RT-PCR will not be performed for several days.

Real-world evidence from over one million COVID-19 vaccinations is consistent with reactivation of the varicella-zoster virus.

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).

Management of hepatitis B virus reactivation due to treatment of COVID-19.

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.

The Anti-COVID-19 Drug Remdesivir Promotes Oncogenic Herpesvirus Reactivation through Regulation of Intracellular Signaling Pathways.

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.

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs.

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.

Case Report: Cytomegalovirus Reactivation and Pericarditis Following ChAdOx1 nCoV-19 Vaccination Against SARS-CoV-2.

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.

Differentials of SARS-CoV-2 Viral RNA Re-positivity in Discharged COVID-19 Patients.

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.

The Outcomes of Patients Incidentally Confirmed with Covid-19 After Cardiac Surgery.

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.

Reactivation of EBV and CMV in Severe COVID-19-Epiphenomena or Trigger of Hyperinflammation in Need of Treatment? A Large Case Series of Critically ill Patients.

BACKGROUND: Reactivation of viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common in critically ill patients and have been described in patients with severe COVID-19. However, it is unclear whether these reactivations are associated with increased mortality and whether targeted treatments are beneficial. METHODS: In a retrospective single-center cohort study, patients with severe COVID-19 treated on our intensive care unit (ICU) were screened for EBV and CMV reactivation as detected by polymerase chain reaction. If present, patient characteristics, temporal connections to severe acute respiratory syndrome coronavirus 2 diagnosis and corticosteroid use, the use of targeted treatments as well as the course of disease and outcome were analyzed. As control group, non-COVID-19 patients with sepsis, treated within the same time period on our ICU, served as control group to compare incidences of viral reactivation. RESULTS: In 19 (16%) of 117 patients with severe COVID-19 treated on our ICU EBV reactivations were identified, comparable 18 (14%) of 126 in the non-COVID-19 control group (P = .672). Similarly, in 11 (9%) of 117 patients CMV reactivations were identified, comparable to the 16 (13%) of 126 in the non-COVID-19 sepsis patients (P = .296). The majority of EBV (58%) and CMV reactivations (55%) were detected in patients under systemic corticosteroid treatment. 7 (37%) of 19 patients with EBV reactivation survived the ICU stay, 2 (29%) of 7 patients with rituximab treatment and 5 (42%) of 12 patients without treatment (P = .568). Five (50%) of 10 patients with CMV reactivation survived the ICU stay, 5 (83%) of 6 patients with ganciclovir treatment and 0 of 4 patients without treatment (P = .048). Follow-up analysis in these patients showed that the initiation of treatment lead to decrease in viral load. CONCLUSION: Critically ill patients with COVID-19 are at a high risk for EBV and CMV reactivations. Whether these reactivations are a cause of hyperinflammation and require targeted treatment remains uncertain. However, in patients with clinical deterioration or signs of hyperinflammation targeted treatment might be beneficial and warrants further studying.

Epstein-Barr Virus Lytic Replication Induces ACE2 Expression and Enhances SARS-CoV-2 Pseudotyped Virus Entry in Epithelial Cells.

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.

Hepatitis B and C screening in hospitalized patients with SARS-CoV-2 infection. / Cribado de infección por virus de la hepatitis B y C en pacientes hospitalizados con infección por SARS-CoV-2.

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.

Clinical characteristics and outcomes of critically ill patients with acute COVID-19 with Epstein-Barr virus reactivation.

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.

Ethacridine inhibits SARS-CoV-2 by inactivating viral particles.

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.

COVID-19 pandemic as a risk factor for the reactivation of herpes viruses.

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.

A broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants.

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.

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress.

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.