Background: Upon SARS-CoV-2 infection, most individuals develop neutralizing antibodies and T-cell immunity. However, some individuals reportedly remain SARS-CoV-2 PCR positive by pharyngeal swabs weeks after recovery. Whether viral RNA in these persistent carriers is contagious and stimulates SARS-CoV-2-specific immune responses is unknown. Methods: This cohort study was conducted between April 3 rd ÀJuly 9 th 2020, recruiting COVID-19 recovered individuals that were symptom-free for at least 14 days. We collected serum for SARS-CoV-2-specific total Ig, IgA and IgM detection by ELISA, pharyngeal swabs (two time points) for ddPCR and PBMCs for anti-SARS-CoV-2 CD8 T-cell dextramer analyses. Findings: We enrolled 203 post-symptomatic participants with a previous RT-PCR-verified SARS-CoV-2 infection. At time point 1, a median of 23 days (range 15À44) after recovery, 26 individuals (12Á8%) were PCR positive. At time point 2, 90 days (median, range 85À105) after recovery, 5 (5Á3%) were positive. There was no difference in SARS-CoV-2 antibody levels between the PCR negative and positive group. The persistent PCR positive group however, had SARS-CoV-2-specific CD8 T-cell responses of significantly increased breadth and magnitude. Assisted contact tracing among persistent PCR positive individuals revealed zero new COVID-19 diagnoses among 757 close contacts. Interpretation: Persistent pharyngeal SARS-CoV-2 PCR positivity in post-symptomatic individuals is associated with elevated cellular immune responses and thus, the viral RNA may represent replicating virus. However, transmission to close contacts was not observed indicating that persistent PCR positive individuals are not contagious at the post-symptomatic stage of the infection.

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as 2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load.

SARS-CoV-2 is a new coronavirus with epicentre in the Hubei-region in China from where it spread globally in late 2019. 1-3 As of 11 March 2020, WHO declared the situation a pandemic. 4 Infection with SARS-CoV-2 leads to COVID-19, a disease ranging from mild respiratory illness to fatal pneumonia with acute respiratory distress syndrome (ARDS). 2,5 SARS-CoV-2 has proven highly contagious and has put an immense strain on healthcare systems worldwide.

Background Although persistent symptoms after Coronavirus disease 2019 (COVID-19) are emerging as a major complication to the infection, data on the diversity and duration of symptoms are needed. Methods Patients aged ≥18 years with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 and hospitalized at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, in the period March 11th to May 15th, were offered follow up after hospitalization. On admission, comprehensive symptom and medical history were collected, including demographic characteristics, duration of symptoms, comorbidities and concomitant medication. At discharge, patients were offered follow-up consultations – either by telephone or in-person visit – at 6 and 12 weeks at our Post-COVID-19 outpatient clinic to assess whether symptoms present at admission had resolved. Results During the inclusion period, 71 patients were admitted with COVID-19. Of these, 10 patients died, 3 were transferred to another region, 4 declined to participate and 5 were lost to follow-up before 12 weeks evaluation. Thus, 49 patients were included. Overall, 96% reported one or more persisting symptoms at 12 weeks follow-up. Main symptoms were fatigue, dyspnea, cough, chemosensory dysfunction, and headache. Conclusion A wide range of persistent symptoms in patients recovering from COVID-19 were present 12 weeks after hospitalization calling for larger descriptive studies and interdisciplinary research collaborations.

Data in the literature regarding the factors that predict unfavorable outcomes in adult herpetic meningoencephalitis (HME) cases are scarce. We conducted a multicenter study in order to provide insights into the predictors of HME outcomes, with special emphasis on the use and timing of antiviral treatment. Samples from 501 patients with molecular confirmation from cerebrospinal fluid were included from 35 referral centers in 10 countries. Four hundred thirty-eight patients were found to be eligible for the analysis. Overall, 232 (52.9%) patients experienced unfavorable outcomes, 44 died, and 188 survived, with sequelae. Age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02 to 1.05), Glasgow Coma Scale score (OR, 0.84; 95% CI, 0.77 to 0.93), and symptomatic periods of 2 to 7 days (OR, 1.80; 95% CI, 1.16 to 2.79) and >7 days (OR, 3.75; 95% CI, 1.72 to 8.15) until the commencement of treatment predicted unfavorable outcomes. The outcome in HME patients is related to a combination of therapeutic and host factors. This study suggests that rapid diagnosis and early administration of antiviral treatment in HME patients are keys to a favorable outcome.

Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS‐CoV‐2 infection is critical for developing treatments for severe COVID‐19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID‐19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL‐6. Using an in vitro stem cell‐based human pDC model, we further demonstrate that pDCs, while not supporting SARS‐CoV‐2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL‐6, IL‐8, CXCL10) cytokines that protect epithelial cells from de novo SARS‐CoV‐2 infection. Via targeted deletion of virus‐recognition innate immune pathways, we identify TLR7‐MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll‐like receptor (TLR)2 is responsible for the inflammatory IL‐6 response. We further show that SARS‐CoV‐2 engages the receptor neuropilin‐1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL‐6 response, suggesting neuropilin‐1 as potential therapeutic target for stimulation of TLR7‐mediated antiviral protection.

Toll-like receptors (TLRs) are a family of pattern recognition receptors and part of the first line of defense against invading microbes. In humans, we know of 10 different TLRs, which are expressed to varying degrees in immune cell subsets. Engaging TLRs through their specific ligands leads to activation of the innate immune system and secondarily priming of the adaptive immune system. Because of these unique properties, TLR agonists have been investigated as immunotherapy in cancer treatment for many years, but in recent years there has also been growing interest in the use of TLR agonists in the context of human immunodeficiency virus type 1 (HIV-1) cure research. The primary obstacle to curing HIV-1 is the presence of a latent viral reservoir in transcriptionally silent immune cells. Due to the very limited transcription of the integrated HIV-1 proviruses, latently infected cells cannot be targeted and cleared by immune effector mechanisms. TLR agonists are very interesting in this context because of their potential dual effects as latency reverting agents (LRAs) and immune modulatory compounds. Here, we review preclinical and clinical data on the impact of TLR stimulation on HIV-1 latency as well as antiviral and HIV-1-specific immunity. We also focus on the promising role of TLR agonists in combination strategies in HIV-1 cure research. Different combinations of TLR agonists and broadly neutralizing antibodies or TLRs agonists as adjuvants in HIV-1 vaccines have shown very encouraging results in non-human primate experiments and these concepts are now moving into clinical testing.

BackgroundThe administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART). MethodsWe did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18-65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per µL. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m² given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials. gov, NCT02850016. It is closed to new participants, and all follow-up is complete.