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1.
Nature ; 602(7898): 671-675, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35016199

RESUMO

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/virologia , Evasão da Resposta Imune/imunologia , Imunização Secundária , SARS-CoV-2/imunologia , Adulto , Anticorpos Monoclonais/imunologia , Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , Bélgica , COVID-19/imunologia , COVID-19/transmissão , ChAdOx1 nCoV-19/administração & dosagem , ChAdOx1 nCoV-19/imunologia , Convalescença , Feminino , Humanos , Masculino , Mutação , Testes de Neutralização , Filogenia , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Viagem
2.
Nature ; 596(7871): 276-280, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237773

RESUMO

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1-5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , Convalescença , Evasão da Resposta Imune/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , Epitopos/química , Epitopos/genética , Epitopos/imunologia , França , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
3.
EMBO J ; 40(24): e108944, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34601723

RESUMO

Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when SARS-CoV-2 spike protein expressed on the surface of infected cells interacts with the ACE2 receptor on neighboring cells. The syncytia forming potential of spike variant proteins remain poorly characterized. Here, we first assessed Alpha (B.1.1.7) and Beta (B.1.351) spread and fusion in cell cultures, compared with the ancestral D614G strain. Alpha and Beta replicated similarly to D614G strain in Vero, Caco-2, Calu-3, and primary airway cells. However, Alpha and Beta formed larger and more numerous syncytia. Variant spike proteins displayed higher ACE2 affinity compared with D614G. Alpha, Beta, and D614G fusion was similarly inhibited by interferon-induced transmembrane proteins (IFITMs). Individual mutations present in Alpha and Beta spikes modified fusogenicity, binding to ACE2 or recognition by monoclonal antibodies. We further show that Delta spike also triggers faster fusion relative to D614G. Thus, SARS-CoV-2 emerging variants display enhanced syncytia formation.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Monoclonais/farmacologia , Células Gigantes/virologia , Mutação , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Animais , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Células Gigantes/efeitos dos fármacos , Células Gigantes/metabolismo , Células HEK293 , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Células Vero , Replicação Viral/efeitos dos fármacos
4.
J Virol ; 98(1): e0135123, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38088562

RESUMO

SARS-CoV-2 variants with undetermined properties have emerged intermittently throughout the COVID-19 pandemic. Some variants possess unique phenotypes and mutations which allow further characterization of viral evolution and Spike functions. Around 1,100 cases of the B.1.640.1 variant were reported in Africa and Europe between 2021 and 2022, before the expansion of Omicron. Here, we analyzed the biological properties of a B.1.640.1 isolate and its Spike. Compared to the ancestral Spike, B.1.640.1 carried 14 amino acid substitutions and deletions. B.1.640.1 escaped binding by some anti-N-terminal domain and anti-receptor-binding domain monoclonal antibodies, and neutralization by sera from convalescent and vaccinated individuals. In cell lines, infection generated large syncytia and a high cytopathic effect. In primary airway cells, B.1.640.1 replicated less than Omicron BA.1 and triggered more syncytia and cell death than other variants. The B.1.640.1 Spike was highly fusogenic when expressed alone. This was mediated by two poorly characterized and infrequent mutations located in the Spike S2 domain, T859N and D936H. Altogether, our results highlight the cytopathy of a hyper-fusogenic SARS-CoV-2 variant, supplanted upon the emergence of Omicron BA.1. (This study has been registered at ClinicalTrials.gov under registration no. NCT04750720.)IMPORTANCEOur results highlight the plasticity of SARS-CoV-2 Spike to generate highly fusogenic and cytopathic strains with the causative mutations being uncharacterized in previous variants. We describe mechanisms regulating the formation of syncytia and the subsequent consequences in a primary culture model, which are poorly understood.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , África , COVID-19/virologia , Pandemias , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/fisiologia , Células Gigantes/virologia
5.
Proc Natl Acad Sci U S A ; 119(20): e2120976119, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35549549

RESUMO

As the coronavirus disease 2019 (COVID-19) pandemic continues, there is a strong need for highly potent monoclonal antibodies (mAbs) that are resistant against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs). Here, we evaluate the potency of the previously described mAb J08 against these variants using cell-based assays and delve into the molecular details of the binding interaction using cryoelectron microscopy (cryo-EM) and X-ray crystallography. We show that mAb J08 has low nanomolar affinity against most VoCs and binds high on the receptor binding domain (RBD) ridge, away from many VoC mutations. These findings further validate the phase II/III human clinical trial underway using mAb J08 as a monoclonal therapy.


Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , SARS-CoV-2 , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Afinidade de Anticorpos , COVID-19/terapia , Humanos , Testes de Neutralização , SARS-CoV-2/imunologia
6.
EMBO J ; 39(23): e106267, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33051876

RESUMO

Severe cases of COVID-19 are associated with extensive lung damage and the presence of infected multinucleated syncytial pneumocytes. The viral and cellular mechanisms regulating the formation of these syncytia are not well understood. Here, we show that SARS-CoV-2-infected cells express the Spike protein (S) at their surface and fuse with ACE2-positive neighboring cells. Expression of S without any other viral proteins triggers syncytia formation. Interferon-induced transmembrane proteins (IFITMs), a family of restriction factors that block the entry of many viruses, inhibit S-mediated fusion, with IFITM1 being more active than IFITM2 and IFITM3. On the contrary, the TMPRSS2 serine protease, which is known to enhance infectivity of cell-free virions, processes both S and ACE2 and increases syncytia formation by accelerating the fusion process. TMPRSS2 thwarts the antiviral effect of IFITMs. Our results show that SARS-CoV-2 pathological effects are modulated by cellular proteins that either inhibit or facilitate syncytia formation.


Assuntos
COVID-19/patologia , Células Gigantes/virologia , Interações Hospedeiro-Patógeno , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Fusão Celular , Linhagem Celular , Chlorocebus aethiops , Células Gigantes/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero/virologia
7.
PLoS Comput Biol ; 19(8): e1011282, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37549192

RESUMO

Because SARS-CoV-2 constantly mutates to escape from the immune response, there is a reduction of neutralizing capacity of antibodies initially targeting the historical strain against emerging Variants of Concern (VoC)s. That is why the measure of the protection conferred by vaccination cannot solely rely on the antibody levels, but also requires to measure their neutralization capacity. Here we used a mathematical model to follow the humoral response in 26 individuals that received up to three vaccination doses of Bnt162b2 vaccine, and for whom both anti-S IgG and neutralization capacity was measured longitudinally against all main VoCs. Our model could identify two independent mechanisms that led to a marked increase in measured humoral response over the successive vaccination doses. In addition to the already known increase in IgG levels after each dose, we identified that the neutralization capacity was significantly increased after the third vaccine administration against all VoCs, despite large inter-individual variability. Consequently, the model projects that the mean duration of detectable neutralizing capacity against non-Omicron VoC is between 348 days (Beta variant, 95% Prediction Intervals PI [307; 389]) and 587 days (Alpha variant, 95% PI [537; 636]). Despite the low neutralization levels after three doses, the mean duration of detectable neutralizing capacity against Omicron variants varies between 173 days (BA.5 variant, 95% PI [142; 200]) and 256 days (BA.1 variant, 95% PI [227; 286]). Our model shows the benefit of incorporating the neutralization capacity in the follow-up of patients to better inform on their level of protection against the different SARS-CoV-2 variants. Trial registration: This clinical trial is registered with ClinicalTrials.gov, Trial IDs NCT04750720 and NCT05315583.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Humanos , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Imunoglobulina G , SARS-CoV-2/genética , Vacinação
8.
Proc Natl Acad Sci U S A ; 118(48)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34819367

RESUMO

Among CD4+ T cells, T helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and are depleted from mucosal sites, which causes damage to the gut barrier, resulting in a microbial translocation-induced systemic inflammation, a hallmark of disease progression. Furthermore, a proportion of latently infected Th17 cells persist long term in the gastrointestinal lymphatic tract where a low-level HIV-1 transcription is observed. This residual viremia contributes to chronic immune activation. Thus, Th17 cells are key players in HIV pathogenesis and viral persistence. It is, however, unclear why these cells are highly susceptible to HIV-1 infection. Th17 cell differentiation depends on the expression of the master transcriptional regulator RORC2, a retinoic acid-related nuclear hormone receptor that regulates specific transcriptional programs by binding to promoter/enhancer DNA. Here, we report that RORC2 is a key host cofactor for HIV replication in Th17 cells. We found that specific inhibitors that bind to the RORC2 ligand-binding domain reduced HIV replication in CD4+ T cells. The depletion of RORC2 inhibited HIV-1 infection, whereas its overexpression enhanced it. RORC2 was also found to promote HIV-1 gene expression by binding to the nuclear receptor responsive element in the HIV-1 long terminal repeats (LTR). In treated HIV-1 patients, RORC2+ CD4 T cells contained more proviral DNA than RORC2- cells. Pharmacological inhibition of RORC2 potently reduced HIV-1 outgrowth in CD4+ T cells from antiretroviral-treated patients. Altogether, these results provide an explanation as to why Th17 cells are highly susceptible to HIV-1 infection and suggest that RORC2 may be a cell-specific target for HIV-1 therapy.


Assuntos
Regulação Viral da Expressão Gênica/genética , HIV-1/crescimento & desenvolvimento , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Adulto , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/metabolismo , Feminino , Expressão Gênica/genética , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Cultura Primária de Células , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/metabolismo , Células Th17/fisiologia , Fatores de Transcrição/metabolismo , Viremia/imunologia , Viremia/virologia , Replicação Viral/fisiologia
9.
J Virol ; 96(14): e0060822, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35862713

RESUMO

Bats are natural reservoirs of numerous coronaviruses, including the potential ancestor of SARS-CoV-2. Knowledge concerning the interaction between coronaviruses and bat cells is sparse. We investigated the ability of primary cells from Rhinolophus and Myotis species, as well as of established and novel cell lines from Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis, and Nyctalus noctula, to support SARS-CoV-2 replication. None of these cells were permissive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species. The resistance to infection was overcome by expression of human ACE2 (hACE2) in three cell lines, suggesting that the restriction to viral replication was due to a low expression of bat ACE2 (bACE2) or the absence of bACE2 binding in these cells. Infectious virions were produced but not released from hACE2-transduced M. myotis brain cells. E. serotinus brain cells and M. myotis nasal epithelial cells expressing hACE2 efficiently controlled viral replication, which correlated with a potent interferon response. Our data highlight the existence of species-specific and cell-specific molecular barriers to viral replication in bat cells. These novel chiropteran cellular models are valuable tools to investigate the evolutionary relationships between bats and coronaviruses. IMPORTANCE Bats are host ancestors of several viruses that cause serious disease in humans, as illustrated by the ongoing SARS-CoV-2 pandemic. Progress in investigating bat-virus interactions has been hampered by a limited number of available bat cellular models. We have generated primary cells and cell lines from several bat species that are relevant for coronavirus research. The various permissivities of the cells to SARS-CoV-2 infection offered the opportunity to uncover some species-specific molecular restrictions to viral replication. All bat cells exhibited a potent entry-dependent restriction. Once this block was overcome by overexpression of human ACE2, which serves at the viral receptor, two bat cell lines controlled well viral replication, which correlated with the inability of the virus to counteract antiviral responses. Other cells potently inhibited viral release. Our novel bat cellular models contribute to a better understanding of the molecular interplays between bat cells and viruses.


Assuntos
Quirópteros , SARS-CoV-2 , Replicação Viral , Enzima de Conversão de Angiotensina 2/genética , Animais , Quirópteros/virologia , Humanos , Receptores Virais/metabolismo , SARS-CoV-2/fisiologia , Especificidade da Espécie , Glicoproteína da Espícula de Coronavírus/metabolismo
10.
Euro Surveill ; 28(25)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37347417

RESUMO

BackgroundThe risk of SARS-CoV-2 (re-)infection remains present given waning of vaccine-induced and infection-acquired immunity, and ongoing circulation of new variants.AimTo develop a method that predicts virus neutralisation and disease protection based on variant-specific antibody measurements to SARS-CoV-2 antigens.MethodsTo correlate antibody and neutralisation titres, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired SARS-CoV-2 immunity. Using the association between antibody and neutralisation titres, we developed a prediction model for SARS-CoV-2-specific neutralisation titres. From predicted neutralising titres, we inferred protection estimates to symptomatic and severe COVID-19 using previously described relationships between neutralisation titres and protection estimates. We estimated population immunity in a French longitudinal cohort of 905 individuals followed from April 2020 to November 2021.ResultsWe demonstrated a strong correlation between anti-SARS-CoV-2 antibodies measured using a low cost high-throughput assay and antibody response capacity to neutralise live virus. Participants with a single vaccination or immunity caused by infection were especially vulnerable to symptomatic or severe COVID-19. While the median reduced risk of COVID-19 from Delta variant infection in participants with three vaccinations was 96% (IQR: 94-98), median reduced risk among participants with infection-acquired immunity was only 42% (IQR: 22-66).ConclusionOur results are consistent with data from vaccine effectiveness studies, indicating the robustness of our approach. Our multiplex serological assay can be readily adapted to study new variants and provides a framework for development of an assay that would include protection estimates.


Assuntos
COVID-19 , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/epidemiologia , França/epidemiologia , Reinfecção , SARS-CoV-2
11.
Am J Transplant ; 22(8): 2099-2103, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35150193

RESUMO

Immunocompromised patients may experience prolonged viral shedding after their initial SARS-CoV-2 infection, however, symptomatic relapses after remission currently remain rare. We herein describe a severe COVID-19 relapse case of a kidney transplant recipient (KTR) following rituximab therapy, 3 months after a moderate COVID-19 infection, despite viral clearance after recovery of the first episode. During the clinical relapse, the diagnosis was established on a broncho-alveolar lavage specimen (BAL) by RT-PCR. The infectivity of the BAL sample was confirmed on a cell culture assay. Whole genome sequencing confirmed the presence of an identical stain (Clade 20A). However, it had an acquired G142D mutation and a larger deletion of 3-amino-acids at position 143-145. These mutations located within the N-terminal domain are suggested to play a role in viral entry. The diagnosis of a COVID-19 relapse should be considered in the setting of unexplained persistent fever and/or respiratory symptoms in KTRs (especially for those after rituximab therapy), even in patients with previous negative naso-pharyngeal SARS-CoV-2 PCR.


Assuntos
COVID-19 , Transplante de Rim , Teste para COVID-19 , Humanos , Transplante de Rim/efeitos adversos , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rituximab/uso terapêutico , SARS-CoV-2/genética
12.
Ann Rheum Dis ; 81(5): 720-728, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35022159

RESUMO

OBJECTIVES: The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases. METHODS: Prospective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety. RESULTS: Sixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses. CONCLUSION: Rituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).


Assuntos
Vacina BNT162 , COVID-19 , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Metotrexato , Estudos Prospectivos , Rituximab , SARS-CoV-2
13.
Nephrol Dial Transplant ; 37(7): 1357-1365, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35104884

RESUMO

BACKGROUND: Patients on maintenance haemodialysis (HD) have an increased risk of severe coronavirus disease 2019 (COVID-19) and a reduced response to vaccines. Data are needed to identify immune correlates of protection in this population. METHODS: Following a COVID-19 outbreak among vaccinated patients in a HD unit, clinical data and serological response to BNT162b2 vaccine were retrospectively recorded. RESULTS: Among 53 patients present in the dialysis room, 14 were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (COVID_Pos) and 39 were not. Compared with uninfected patients, COVID_Pos patients more frequently had additional causes of immunosuppression (50% versus 21%; P = .046) and were more often scheduled on the Monday-Wednesday-Friday (MWF) shift (86% versus 39%; P = .002). Moreover, COVID_Pos had lower anti-spike (S) immunoglobulin G (IgG) titres than uninfected patients {median 24 BAU/mL [interquartile range (IQR) 3-1163] versus 435 [99-2555]; P = .001} and lower neutralization titres [median 108 (IQR 17-224) versus 2483 (481-43 908); P = .007]. Anti-S and neutralization antibody titres are correlated (r = 0.92, P < .001). In multivariable analysis, an MWF schedule {odds ratio [OR] 10.74 [95% confidence interval (CI) 1.9-93.5], P = .014} and anti-S IgG titres 1 month before the outbreak [<205 BAU/mL: OR 0.046 (95% CI 0.002-0.29), P = .006] were independently associated with COVID-19 infection. None of the patients with anti-S IgG >284 BAU/mL got infected. Ten of 14 COVID_Pos patients were treated with casirivimab and imdevimab. No patient developed severe disease. CONCLUSIONS: Anti-S IgG titre measured prior to exposure correlates to protection from SARS-CoV-2 infection in HD patients. BNT162b2 vaccination alone or in combination with monoclonal antibodies prevented severe COVID-19.


Assuntos
COVID-19 , Vacinas Virais , Anticorpos Monoclonais Humanizados , Anticorpos Antivirais , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Surtos de Doenças , Unidades Hospitalares de Hemodiálise , Humanos , Imunoglobulina G , Diálise Renal , Estudos Retrospectivos , SARS-CoV-2
14.
J Infect Dis ; 224(9): 1489-1499, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34282461

RESUMO

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. METHODS: We developed a multiplex serological test for measuring antibodies to 5 SARS-CoV-2 antigens and the spike proteins of seasonal coronaviruses. We measured antibody responses in cohorts of hospitalized patients and healthcare workers followed for up to 11 months after symptoms. A mathematical model of antibody kinetics was used to quantify the duration of antibody responses. Antibody response data were used to train algorithms for estimating time since infection. RESULTS: One year after symptoms, we estimate that 36% (95% range, 11%-94%) of anti-Spike immunoglobulin G (IgG) remains, 31% (95% range, 9%-89%) anti-RBD IgG remains, and 7% (1%-31%) of anti-nucleocapsid IgG remains. The multiplex assay classified previous infections into time intervals of 0-3 months, 3-6 months, and 6-12 months. This method was validated using data from a seroprevalence survey in France, demonstrating that historical SARS-CoV-2 transmission can be reconstructed using samples from a single survey. CONCLUSIONS: In addition to diagnosing previous SARS-CoV-2 infection, multiplex serological assays can estimate the time since infection, which can be used to reconstruct past epidemics.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/imunologia , Testes Sorológicos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos , Especificidade de Anticorpos , COVID-19/epidemiologia , Feminino , França/epidemiologia , Humanos , Imunoglobulina G/sangue , Cinética , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Adulto Jovem
15.
Clin Infect Dis ; 73(6): e1337-e1344, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-33851216

RESUMO

BACKGROUND: Humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs within the first weeks after coronavirus disease 2019 (COVID-19). Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution over time after COVID-19 as well as efficiency against novel variants are poorly characterized. METHODS: In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3 and 6 months postinfection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-spike (S) and anti-nucleocapsid (NP) immunoglobulin G (IgG). RESULTS: Levels of seroneutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with seroneutralization, and this correlation was stronger for anti-S than for anti-NP antibodies. The level of seroneutralization quantified at 6 months correlated with markers of initial severity, notably admission to intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against the D614G, B.1.1.7, and P.1 variants but significantly weaker activity against the B.1.351 variant. CONCLUSIONS: Decrease in IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1.1.7, and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was, however, observed for the B.1.351 variant.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Hospitalização , Humanos , Estudos Prospectivos , Glicoproteína da Espícula de Coronavírus
17.
AIDS Res Ther ; 17(1): 15, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398104

RESUMO

BACKGROUND: Increased intestinal barrier permeability and subsequent gut microbial translocation are significant contributors to inflammatory non-AIDS comorbidities in people living with HIV (PLWH). Evidence in animal models have shown that markers of intestinal permeability and microbial translocation vary over the course of the day and are affected by food intake and circadian rhythms. However, daily variations of these markers are not characterized yet in PLWH. Herein, we assessed the variation of these markers over 24 h in PLWH receiving antiretroviral therapy (ART) in a well-controlled environment. METHODS: As in Canada, PLWH are predominantly men and the majority of them are now over 50 years old, we selected 11 men over 50 receiving ART with undetectable viremia for more than 3 years in this pilot study. Blood samples were collected every 4 h over 24 h before snacks/meals from 8:00 in the morning to 8:00 the next day. All participants consumed similar meals at set times, and had a comparable amount of sleep, physical exercise and light exposure. Plasma levels of bacterial lipopolysaccharide (LPS) and fungal (1→3)-ß-D-Glucan (BDG) translocation markers, along with markers of intestinal damage fatty acid binding protein (I-FABP) and regenerating islet-derived protein-3α (REG3α) were assessed by ELISA or the fungitell assay. RESULTS: Participants had a median age of 57 years old (range 50 to 63). Plasma levels of BDG and REG3α did not vary significantly over the course of the study. In contrast, a significant increase of LPS was detected between 12:00 and 16:00 (Z-score: - 1.15 ± 0.18 vs 0.16 ± 0.15, p = 0.02), and between 12:00 and 24:00 (- 1.15 ± 0.18 vs 0.89 ± 0.26, p < 0.001). The plasma levels of I-FABP at 16:00 (- 0.92 ± 0.09) were also significantly lower, compared to 8:00 the first day (0.48 ± 0.26, p = 0.002), 4:00 (0.73 ± 0.27, p < 0.001) or 8:00 on secondary day (0.88 ± 0.27, p < 0.001). CONCLUSIONS: Conversely to the fungal translocation marker BDG and the gut damage marker REG3α, time of blood collection matters for the proper evaluation for LPS and I-FABP as markers for the risk of inflammatory non-AIDS co-morbidities. These insights are instrumental for orienting clinical investigations in PLWH.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Translocação Bacteriana , Fungos/fisiologia , Microbioma Gastrointestinal , Infecções por HIV/tratamento farmacológico , Infecções por HIV/microbiologia , Antígenos de Fungos/sangue , Translocação Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Fungos/efeitos dos fármacos , Infecções por HIV/epidemiologia , Humanos , Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto
18.
PLoS Pathog ; 13(7): e1006460, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28727807

RESUMO

HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/imunologia , Digoxina/farmacologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Integração Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
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