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1.
Cell ; 185(23): 4333-4346.e14, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36257313

RESUMO

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection.


Assuntos
Linfócitos B , COVID-19 , Vacinas Virais , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , SARS-CoV-2 , Vacinação , Linfócitos B/imunologia , Vacinas de mRNA
2.
Cell ; 182(5): 1077-1092, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32846157

RESUMO

Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences.


Assuntos
Doenças Transmissíveis Emergentes/epidemiologia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , COVID-19 , Doenças Transmissíveis Emergentes/prevenção & controle , Doenças Transmissíveis Emergentes/transmissão , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Demografia , Meio Ambiente , Interações Hospedeiro-Patógeno , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão
3.
Immunity ; 56(12): 2665-2669, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38091944

RESUMO

Vaccines have stemmed many infectious diseases, but when SARS-CoV-2 emerged, traditional vaccine development would not have been fast enough. This year's Nobel Prize in Physiology or Medicine recognizes work that enabled the rapid development of mRNA vaccines, which halted the COVID-19 pandemic. The feat was a product of basic biological insights coupled with technological innovations, which have transformed vaccine design.


Assuntos
COVID-19 , Vacinas , Humanos , Vacinas de mRNA , Pandemias/prevenção & controle , COVID-19/prevenção & controle , Vacinas contra COVID-19/genética , Vacinas/genética
4.
Immunity ; 54(12): 2676-2680, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34739870

RESUMO

The 2005 Immunity paper by Karikó et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/fisiologia , Desenvolvimento de Vacinas/história , Vacinas de mRNA/imunologia , Animais , História do Século XXI , Humanos , RNA Mensageiro/imunologia , Organização Mundial da Saúde
5.
Cell ; 183(3): 837, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33125895
6.
Nature ; 606(7913): 375-381, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35650437

RESUMO

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.


Assuntos
Fármacos Anti-HIV , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/imunologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Amplamente Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Método Duplo-Cego , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/efeitos adversos , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/isolamento & purificação , Humanos , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologia
7.
Nature ; 606(7913): 368-374, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35418681

RESUMO

HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4+ T cells1. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells2,3. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml-1. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.


Assuntos
Antirretrovirais , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Carga Viral , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/virologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Provírus/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Latência Viral/efeitos dos fármacos
8.
Nat Immunol ; 16(6): 584-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25990814

RESUMO

The persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virologic remission in HIV-infected individuals after antiretroviral therapy (ART) is discontinued, even if plasma viremia has been successfully suppressed for prolonged periods of time. Numerous approaches aimed at eradicating the virus, as well as maintaining its prolonged suppression in the absence of ART, have had little success. A better understanding of the pathophysiologic nature of HIV reservoirs and the impact of various interventions on their persistence is essential for the development of successful therapeutic strategies against HIV or the long-term control of infection. Here, we discuss the persistent HIV reservoir as a barrier to cure as well as the current therapeutic strategies aimed at eliminating or controlling the virus in the absence of ART.


Assuntos
Antirretrovirais/uso terapêutico , Reservatórios de Doenças/virologia , Infecções por HIV/tratamento farmacológico , HIV/fisiologia , Latência Viral , HIV/efeitos dos fármacos , Infecções por HIV/transmissão , Humanos , Carga Viral/efeitos dos fármacos , Ativação Viral
9.
Immunity ; 47(4): 599-603, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045889

RESUMO

Development of a universal influenza vaccine is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. To facilitate this goal, we convened a workshop in Rockville, Maryland to identify knowledge gaps in influenza research and develop strategies to fill them.


Assuntos
Modelos Animais de Doenças , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Animais , Furões , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Influenza Humana/virologia , National Institute of Allergy and Infectious Diseases (U.S.) , Estados Unidos
10.
Proc Natl Acad Sci U S A ; 120(29): e2305896120, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37428933

RESUMO

Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV gag mRNA, the Spike-SIVCT.745 (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with SSt+gag mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to SSt mRNA alone. Furthermore, mice immunized with SSt+gag mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.


Assuntos
COVID-19 , Vírus da Imunodeficiência Símia , Humanos , Animais , Camundongos , Vacinas contra COVID-19/genética , Anticorpos Antivirais , SARS-CoV-2/genética , COVID-19/prevenção & controle , Anticorpos Neutralizantes , Glicoproteína da Espícula de Coronavírus/genética , Vírus da Imunodeficiência Símia/genética
11.
PLoS Pathog ; 19(3): e1011209, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36897929

RESUMO

CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-ß, promote the differentiation of CD4+ T cells into a distinct subset α4ß7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.


Assuntos
Linfócitos T CD4-Positivos , Infecções por HIV , Humanos , Fator de Crescimento Transformador beta , Tretinoína/farmacologia , Diferenciação Celular , Memória Imunológica , Receptores CCR5
12.
Nat Immunol ; 14(11): 1104-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24145780

RESUMO

As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas.


Assuntos
Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , HIV/imunologia , Pandemias , Vacinas contra a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/imunologia , Antígenos Virais/imunologia , Terapia Antirretroviral de Alta Atividade , Humanos , Estados Unidos/epidemiologia
13.
Nat Immunol ; 14(12): 1256-65, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24162774

RESUMO

The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin α4ß7 on T cells. We found that gp120 also bound to and signaled through α4ß7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through α4ß7 resulted in increased expression of the immunosuppressive cytokine TGF-ß1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Proteína gp120 do Envelope de HIV/imunologia , Receptores Fc/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células CHO , Células Cultivadas , Técnicas de Cocultura , Cricetinae , Cricetulus , Citometria de Fluxo , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/genética , HIV-1/imunologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Integrinas/genética , Integrinas/imunologia , Integrinas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica/imunologia , Receptores Fc/genética , Receptores Fc/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
14.
Proc Natl Acad Sci U S A ; 119(47): e2213361119, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36322776

RESUMO

Severe COVID-19 is characterized by a prothrombotic state associated with thrombocytopenia, with microvascular thrombosis being almost invariably present in the lung and other organs at postmortem examination. We evaluated the presence of antibodies to platelet factor 4 (PF4)-polyanion complexes using a clinically validated immunoassay in 100 hospitalized patients with COVID-19 with moderate or severe disease (World Health Organization score, 4 to 10), 25 patients with acute COVID-19 visiting the emergency department, and 65 convalescent individuals. Anti-PF4 antibodies were detected in 95 of 100 hospitalized patients with COVID-19 (95.0%) irrespective of prior heparin treatment, with a mean optical density value of 0.871 ± 0.405 SD (range, 0.177 to 2.706). In contrast, patients hospitalized for severe acute respiratory disease unrelated to COVID-19 had markedly lower levels of the antibodies. In a high proportion of patients with COVID-19, levels of all three immunoglobulin (Ig) isotypes tested (IgG, IgM, and IgA) were simultaneously elevated. Antibody levels were higher in male than in female patients and higher in African Americans and Hispanics than in White patients. Anti-PF4 antibody levels were correlated with the maximum disease severity score and with significant reductions in circulating platelet counts during hospitalization. In individuals convalescent from COVID-19, the antibody levels returned to near-normal values. Sera from patients with COVID-19 induced higher levels of platelet activation than did sera from healthy blood donors, but the results were not correlated with the levels of anti-PF4 antibodies. These results demonstrate that the vast majority of patients with severe COVID-19 develop anti-PF4 antibodies, which may play a role in the clinical complications of COVID-19.


Assuntos
COVID-19 , Trombocitopenia , Humanos , Masculino , Feminino , Fator Plaquetário 4 , Heparina , Anticorpos , Fatores Imunológicos , Índice de Gravidade de Doença
15.
Proc Natl Acad Sci U S A ; 119(28): e2204607119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35759653

RESUMO

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV , Formação de Anticorpos , Linfócitos B , COVID-19 , RNA Mensageiro , SARS-CoV-2 , Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Linfócitos B/imunologia , COVID-19/prevenção & controle , Humanos , Imunidade Celular , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Vacinação
16.
J Infect Dis ; 228(4): 422-425, 2023 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-37035891

RESUMO

The global experience with COVID-19 holds important lessons for preparing for, and responding to, future emergences of pathogens with pandemic potential.


Assuntos
Defesa Civil , Saúde Global , Pandemias , Humanos , COVID-19 , Pandemias/prevenção & controle , Defesa Civil/educação , Defesa Civil/tendências , Saúde Global/educação , Saúde Global/tendências , Conhecimento
17.
J Infect Dis ; 227(12): 1433-1441, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35876700

RESUMO

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.


Assuntos
Pandemias , Vacinas , Surtos de Doenças , National Institute of Allergy and Infectious Diseases (U.S.) , Pandemias/prevenção & controle , Desenvolvimento de Vacinas , Doenças Transmissíveis/epidemiologia
19.
Nature ; 543(7646): 559-563, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28289286

RESUMO

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8ß monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/terapia , HIV/imunologia , Imunização Passiva , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Vírus da Imunodeficiência Símia/imunologia , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Terapia Combinada , Modelos Animais de Doenças , Feminino , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/virologia , Meia-Vida , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/isolamento & purificação , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Viremia/imunologia , Viremia/terapia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
20.
Ann Intern Med ; 175(1): 119-126, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724404

RESUMO

As the fourth wave of the SARS-CoV-2 pandemic encircles the globe, there remains an urgent challenge to identify safe and effective treatment and prevention strategies that can be implemented in a range of health care and clinical settings. Substantial advances have been made in the use of anti-SARS-CoV-2 antibodies to mitigate the morbidity and mortality associated with COVID-19. On 15 June 2021, the National Institutes of Health, in collaboration with the U.S. Food and Drug Administration, convened a virtual summit to summarize existing knowledge on anti-SARS-CoV-2 antibodies and to identify key unanswered scientific questions to further catalyze the clinical development and implementation of antibodies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , COVID-19/terapia , SARS-CoV-2/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , COVID-19/imunologia , Humanos , Imunização Passiva/efeitos adversos , National Institutes of Health (U.S.) , Estados Unidos , United States Food and Drug Administration , Soroterapia para COVID-19
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