While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

The aim of the study was to describe the relationship between preterm delivery (PTD; < 37 weeks of gestation) and antiretroviral therapy in a single-centre cohort of pregnant women with HIV infection. MethodsA retrospective analysis of data for 331 women who received care in a dedicated HIV antenatal clinic between 1996 and 2010 was carried out. Data on first CD4 cell count and viral load (HIV-1 RNA copies/mL) recorded in pregnancy, class and timing of antiretroviral therapy, gestational age at delivery, and risk factors for and causes of PTD were available from a clinical database. ResultsOverall, 13.0% of deliveries were preterm, of which 53% were severe preterm (< 34 weeks of gestation). The lowest rate of PTD was observed in women treated with zidovudine monotherapy (6.2%). Higher rates of PTD were observed in women starting combination antiretroviral therapy (cART) in pregnancy compared with women conceiving while on cART [odds ratio (OR) 2.52; 95% confidence interval (CI) 1.22-5.20; P = 0.011]. Of the women who were eligible for zidovudine monotherapy on the basis of CD4 counts and HIV viral load but who were treated with short-term cART to prevent HIV mother-to-child transmission, 28.6% delivered preterm. Women on short-term cART remained at the highest risk of PTD compared with zidovudine monotherapy in multivariate analysis (OR 5.00; 95% CI 1.49-16.79; P = 0.015). ConclusionsThe causes of PTD are multiple and poorly understood. The timing of initiation and type of antiretroviral therapy administered during pregnancy appear to contribute to PTD risk. Understanding this association should improve the safety of antiretroviral therapy in pregnancy without increasing the risk of transmission.

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The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.

It is currently unknown how Post-COVID-19 Syndrome (PCS) may affect those infected with SARS-CoV-2. This longitudinal study reports on healthcare staff who tested positive for SARS-CoV-2 between March-April 2020 and follows their antibody titres and symptomatology. Over half (n=21/38) had PCS at 7-8 months. There was no statistically significant difference between initial RT-PCR viral titres or serial antibody levels between those who did and did not develop PCS. This study highlights the relative commonality of PCS in healthcare workers and this should be considered in vaccination scheduling and workforce planning to allow adequate frontline staffing numbers.

BackgroundPregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.MethodsProspective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.FindingsThere was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.InterpretationThere is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

The use of combination antiretroviral therapy for the prevention of mother to child transmission of HIV infection has achieved vertical HIV transmission rates of <1%. The use of these drugs is not without risk to the mother and infant. Pregnant women with HIV-infection are at high risk of preterm birth (PTB <37 weeks), with 2-4-fold the risk of uninfected women. There is accumulating evidence that certain combinations are associated with higher rates of PTB that others or no antiretroviral treatment. Understanding the pathogenesis of PTB in this group of women will be essential to target preventative strategies in the face of increasing HIV prevalence and rapidly expanding mother-to-child-transmission prevention programmes.