RESUMO
This Medical News story discusses a recent study that found people who are immunocompromised clear SARS-CoV-2 at varying rates.
Assuntos
COVID-19 , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , Hospedeiro Imunocomprometido/imunologia , SARS-CoV-2/imunologia , Carga Viral/imunologiaRESUMO
BACKGROUND: Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial (NCT02616874), combined a T-cell vaccine with romidepsin (RMD), a cancer-drug that was used to promote HIV-1 latency reversal and which has also been shown to have beneficial effects on neurofunction. We conducted longitudinal plasma proteomics analyses in trial participants to define biomarkers associated with virus control during monitored antiretroviral pause (MAP) and to identify novel therapeutic targets that can improve future cure strategies. METHODS: BCN02 was a phase I, open-label, single-arm clinical trial in early-treated, HIV infected individuals. Longitudinal plasma proteomes were analyzed in 11 BCN02 participants, including 8 participants that showed a rapid HIV-1 plasma rebound during a monitored antiretroviral pause (MAP-NC, 'non-controllers') and 3 that remained off ART with sustained plasma viremia <2000 copies/ml (MAP-C, 'controllers'). Inflammatory and neurological proteomes in plasma were evaluated and integration data analysis (viral and neurocognitive parameters) was performed. Validation studies were conducted in a cohort of untreated HIV-1+ individuals (n = 96) and in vitro viral replication assays using an anti-CD33 antibody were used for functional validation. FINDINGS: Inflammatory plasma proteomes in BCN02 participants showed marked longitudinal alterations. Strong proteome differences were also observed between MAP-C and MAP-NC, including in baseline timepoints. CD33/Siglec-3 was the unique plasma marker with the ability to discriminate between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Analyses in an untreated cohort of PLWH confirmed the positive correlation between viral parameters and CD33 plasma levels, as well as PBMC gene expression. Finally, adding an anti-CD33 antibody to in vitro virus cultures significantly reduced HIV-1 replication and proviral levels in T cells and macrophages. INTERPRETATION: This study indicates that CD33/Siglec-3 may serve as a predictor of HIV-1 control and as potential therapeutic tool to improve future cure strategies. FUNDING: Spanish Science and Innovation Ministry (SAF2017-89726-R and PID2020-119710RB-I00), NIH (P01-AI131568), European Commission (GA101057548) and a Grifols research agreement.
Assuntos
Biomarcadores , Infecções por HIV , HIV-1 , Carga Viral , Humanos , Linfócitos T CD4-Positivos , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/imunologia , Soropositividade para HIV , HIV-1/genética , HIV-1/fisiologia , Leucócitos Mononucleares , Proteoma , Proteômica , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Vacinação , Carga Viral/efeitos dos fármacos , Carga Viral/genética , Carga Viral/imunologia , Fármacos Anti-HIV , Biomarcadores/sangue , Biomarcadores/metabolismoAssuntos
Fármacos Anti-HIV , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Carga Viral , Fármacos Anti-HIV/imunologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Carga Viral/efeitos dos fármacos , Carga Viral/imunologiaRESUMO
The BNT162b2 COVID-19 vaccine has been shown to reduce viral load of breakthrough infections (BTIs), an important factor affecting infectiousness. This viral-load protective effect has been waning with time post the second vaccine and later restored with a booster shot. It is currently unclear though for how long this regained effectiveness lasts. Analyzing Ct values of SARS-CoV-2 qRT-PCR tests of over 22,000 infections during a Delta-variant-dominant period in Israel, we find that this viral-load reduction effectiveness significantly declines within months post the booster dose. Adjusting for age, sex and calendric date, Ct values of RdRp gene initially increases by 2.7 [CI: 2.3-3.0] relative to unvaccinated in the first month post the booster dose, yet then decays to a difference of 1.3 [CI: 0.7-1.9] in the second month and becomes small and insignificant in the third to fourth months. The rate and magnitude of this post-booster decline in viral-load reduction effectiveness mirror those observed post the second vaccine. These results suggest rapid waning of the booster's effectiveness in reducing infectiousness, possibly affecting community-level spread of the virus.
Assuntos
Vacina BNT162/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunização Secundária/métodos , SARS-CoV-2/imunologia , Carga Viral/imunologia , Adulto , Algoritmos , Vacina BNT162/administração & dosagem , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunização Secundária/estatística & dados numéricos , Imunogenicidade da Vacina/imunologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Fatores de Tempo , Resultado do Tratamento , Vacinação/métodos , Vacinação/estatística & dados numéricosRESUMO
Studies comparing SARS-CoV-2 nasopharyngeal (NP) viral load (VL) according to virus variant and host vaccination status have yielded inconsistent results. We conducted a single center prospective study between July and September 2021 at the drive-through testing center of the Toulouse University Hospital. We compared the NP VL of 3775 patients infected by the Delta (n = 3637) and Alpha (n = 138) variants, respectively. Patient's symptoms and vaccination status (2619 unvaccinated, 636 one dose and 520 two doses) were recorded. SARS-CoV-2 RNA testing and variant screening were assessed by using Thermo Fisher® TaqPath™ COVID-19 and ID solutions® ID™ SARS-CoV-2/VOC evolution Pentaplex assays. Delta SARS-CoV-2 infections were associated with higher VL than Alpha (coef = 0.68; p ≤ 0.01) independently of patient's vaccination status, symptoms, age and sex. This difference was higher for patients diagnosed late after symptom onset (coef = 0.88; p = 0.01) than for those diagnosed early (coef = 0.43; p = 0.03). Infections in vaccinated patients were associated with lower VL (coef = -0.18; p ≤ 0.01) independently of virus variant, symptom, age and sex. Our results suggest that Delta infections could lead to higher VL and for a longer period compared to Alpha infections. By effectively reducing the NP VL, vaccination could allow for limiting viral spread, even with the Delta variant.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , RNA Viral/genética , SARS-CoV-2/imunologia , Vacinação/estatística & dados numéricos , Carga Viral/imunologia , Carga Viral/estatística & dados numéricos , Adulto , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Hospitalização , Humanos , Masculino , Nasofaringe/virologia , Estudos Prospectivos , SARS-CoV-2/genética , Carga Viral/métodos , Adulto JovemRESUMO
Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells > 350/mL and <500/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (<10 copies/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients.
Assuntos
Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Raltegravir Potássico/uso terapêutico , Carga Viral/imunologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Viral/metabolismo , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , Humanos , Cinética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Fenótipo , Raltegravir Potássico/farmacologia , Carga Viral/efeitos dos fármacosRESUMO
Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterologous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflammatory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2. There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load.
Assuntos
Imunidade Adaptativa , Fatores Etários , COVID-19/imunologia , Imunidade Heteróloga , Imunidade Inata , SARS-CoV-2/imunologia , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Coagulação Sanguínea/imunologia , Criança , Proteção Cruzada , Reações Cruzadas , Endotélio/imunologia , Humanos , Gravidade do Paciente , Serina Endopeptidases/metabolismo , Carga Viral/imunologiaRESUMO
Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry. In a longitudinal analysis during acute HCV infection, frequencies of activated CD38+ iNKT cells reproducibly declined in spontaneously resolving patients, whereas they were persistently elevated in patients progressing to chronic infection. During the first year of infection, the frequency of activated CD38+ or CD69+ iNKT cells strongly correlated with alanine transaminase levels with particularly pronounced correlations in spontaneously resolving patients. Increased frequencies of activated iNKT cells in chronic HCV infection were confirmed in cross-sectional analyses of PWID with chronic or spontaneously resolved HCV infection; however, no apparent functional differences were observed with various stimulation protocols. Our data suggest that iNKT cells are activated during acute hepatitis C and that activation is sustained in chronic infection. The correlation between the frequency of activated iNKT cells and alanine transaminase may point toward a role of iNKT cells in liver damage.
Assuntos
ADP-Ribosil Ciclase 1/análise , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Hepacivirus , Hepatite C , Lectinas Tipo C/análise , Ativação Linfocitária/imunologia , Células T Matadoras Naturais , Doença Aguda , Alanina Transaminase/sangue , Estudos Transversais , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C/sangue , Hepatite C/fisiopatologia , Hepatite C/virologia , Humanos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/virologia , Infecção Persistente/imunologia , Infecção Persistente/virologia , Remissão Espontânea , Carga Viral/imunologiaRESUMO
Persons living with HIV (PLWH) are at higher risk of developing secondary illnesses than their uninfected counterparts, suggestive of a dysfunctional immune system in these individuals. Upon exposure to pathogens, monocytes undergo epigenetic remodeling that results in either a trained or a tolerant phenotype, characterized by hyper-responsiveness or hypo-responsiveness to secondary stimuli, respectively. We utilized CD14+ monocytes from virally suppressed PLWH and healthy controls for in vitro analysis following polarization of these cells toward a pro-inflammatory monocyte-derived macrophage (MDM) phenotype. We found that in PLWH-derived MDMs, pro-inflammatory signals (TNFA, IL6, IL1B, miR-155-5p, and IDO1) dominate over negative feedback signals (NCOR2, GSN, MSC, BIN1, and miR-146a-5p), favoring an abnormally trained phenotype. The mechanism of this reduction in negative feedback involves the attenuated expression of IKZF1, a transcription factor required for de novo synthesis of RELA during LPS-induced inflammatory responses. Furthermore, restoring IKZF1 expression in PLWH-MDMs partially reinstated expression of negative regulators of inflammation and lowered the expression of pro-inflammatory cytokines. Overall, this mechanism may provide a link between dysfunctional immune responses and susceptibility to co-morbidities in PLWH with low or undetectable viral load.
Assuntos
Suscetibilidade a Doenças/imunologia , Infecções por HIV/imunologia , Fator de Transcrição Ikaros/metabolismo , Macrófagos/imunologia , Fator de Transcrição RelA/metabolismo , Fármacos Anti-HIV/administração & dosagem , Estudos de Casos e Controles , Citocinas/metabolismo , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , HIV/imunologia , HIV/isolamento & purificação , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Voluntários Saudáveis , Humanos , Inflamação/sangue , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Transcrição RelA/genética , Carga Viral/efeitos dos fármacos , Carga Viral/imunologiaRESUMO
Antigen-specific tissue-resident memory T cells (Trms) and neutralizing IgA antibodies provide the most effective protection of the lungs from viral infections. To induce those essential components of lung immunity against SARS-CoV-2, we tested various immunization protocols involving intranasal delivery of a novel Modified Vaccinia virus Ankara (MVA)-SARS-2-spike vaccine candidate. We show that a single intranasal MVA-SARS-CoV-2-S application in mice strongly induced pulmonary spike-specific CD8+ T cells, albeit restricted production of neutralizing antibodies. In prime-boost protocols, intranasal booster vaccine delivery proved to be crucial for a massive expansion of systemic and lung tissue-resident spike-specific CD8+ T cells and the development of Th1 - but not Th2 - CD4+ T cells. Likewise, very high titers of IgG and IgA anti-spike antibodies were present in serum and broncho-alveolar lavages that possessed high virus neutralization capacities to all current SARS-CoV-2 variants of concern. Importantly, the MVA-SARS-2-spike vaccine applied in intramuscular priming and intranasal boosting treatment regimen completely protected hamsters from developing SARS-CoV-2 lung infection and pathology. Together, these results identify intramuscular priming followed by respiratory tract boosting with MVA-SARS-2-S as a promising approach for the induction of local, respiratory as well as systemic immune responses suited to protect from SARS-CoV-2 infections.
Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Vetores Genéticos , Imunização Secundária , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Vacinação , Vacinas de Subunidades Antigênicas/imunologia , Vaccinia virus/imunologia , Células Vero , Carga Viral/imunologiaRESUMO
Despite the benefits achieved by the widespread availability of modern antiretroviral therapy (ART), HIV RNA integration into the host cell genome is responsible for the creation of latent HIV reservoirs, and represents a significant impediment to completely eliminating HIV infection in a patient via modern ART alone. Several methods to measure HIV reservoir size exist; however, simpler, cheaper, and faster tools are required in the quest for total HIV cure. Over the past few years, measurement of HIV-specific antibodies has evolved into a promising option for measuring HIV reservoir size, as they can be measured via simple, well-known techniques such as the western blot and enzyme-linked immunosorbent assay (ELISA). In this article, we re-visit the dynamic evolution of HIV-1-specific antibodies and the factors that may influence their levels in the circulation of HIV-positive individuals. Then, we describe the currently-known relationship between HIV-1-specific antibodies and HIV reservoir size based on study of data from contemporary literature published during the past 5 years. We conclude by highlighting current trends, and discussing the individual HIV-specific antibody that is likely to be the most reliable antibody for potential future utilization for quantification of HIV reservoir size.
Assuntos
Anticorpos Anti-HIV/sangue , Soropositividade para HIV/diagnóstico , HIV-1/imunologia , Latência Viral/imunologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Estudos de Viabilidade , Anticorpos Anti-HIV/imunologia , Soropositividade para HIV/sangue , Soropositividade para HIV/imunologia , Soropositividade para HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , RNA Viral/sangue , Carga Viral/imunologia , Replicação Viral/imunologiaRESUMO
Different methods for producing bulk quantities of concentrated and purified SARS-CoV-2 for the use as antigens and for the research into COVID-19 biology were tested.
Assuntos
Teste para COVID-19/métodos , COVID-19/diagnóstico , SARS-CoV-2/imunologia , Carga Viral/imunologia , Vírion/imunologia , Animais , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/isolamento & purificação , Anticorpos Antivirais/metabolismo , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Convalescença , Células Epiteliais/virologia , Humanos , Soros Imunes/química , SARS-CoV-2/genética , SARS-CoV-2/crescimento & desenvolvimento , Suínos , Células Vero , Carga Viral/genética , Proteínas Virais/imunologia , Proteínas Virais/isolamento & purificação , Proteínas Virais/metabolismo , Vírion/genética , Vírion/crescimento & desenvolvimento , Replicação ViralRESUMO
Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , Filogenia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Brasil , ChAdOx1 nCoV-19 , Estudos de Coortes , Relação Dose-Resposta Imunológica , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinação , Carga Viral/imunologia , Adulto JovemRESUMO
The aim of the present study was to explore the effect of hepatitis B virus on T lymphocyte and its subsets in different ALT states, and elucidate the immunological mechanism of ALT basing antiviral therapy for hepatitis B. 363 chronic hepatitis B patients were selected as the study subjects. According to ALT abnormalities, the patients were divided into three study groups. ALT normal group 131 cases, normal⦠ALT < 2 times of upper limit group 110 cases, ALT ≥ 2 times of upper limit group 122 cases. Entecavir was given to the ALT ≥ 2 times of upper limit group patients and followed up for 24 weeks. The hepatitis B antigen antibody parameters were measured by chemiluminescence immunoassay analyzer, the liver function parameters were measured by automatic biochemical analyzer, the hepatitis B virus load were measured by quantitative PCR analyzer, T lymphocytes were detected by flow cytometry, the level of IL-2, IFN-γ, IL-4 and IL-10 were detected by enzyme-linked immunosorbent assay. Detecting the influence of different hepatitis B viru loads in different groups on immunological indexes, and the virological and immunological indexes changes in before and after antiviral therapy patients. In the ALT normal group, different virus load hepatitis B virus had minor effect on T lymphocytes and their subsets (P > 0.05). In the ALT ≥ double upper limit of normal group. with the virus load increased, The total number of T lymphocytes, CD3+ CD4 + T lymphocytes decreased, (P < 0.05)CD3+ CD8 + T lymphocytes increased(P < 0.05). With the virus load increased the cytokines IL-2, IFN-γ which reflect the Th1 lymphocytes increased(P < 0.05), the cytokines IL-4ãIL-10 which reflect the Th2 lymphocytes decreased(P < 0.05). Before and after 24 weeks of entecavir treatment, the patient's HBV-DNA decreased significantly(P < 0.05) and the body's immune function improved significantly. (P < 0.05)The influence of hepatitis B virus on immune function is different in different ALT states. Therefore, the scientific significance of ALT grouping in the hepatitis B treatment can be clarified from the immunological point.
Assuntos
Alanina Transaminase/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Feminino , Antígenos E da Hepatite B/imunologia , Antígenos E da Hepatite B/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Carga Viral/imunologia , Adulto JovemRESUMO
SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-ß (TGFß) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFß-dependent manner. Our data reveal that an untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.
Assuntos
COVID-19/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Fator de Crescimento Transformador beta/imunologia , Atlas como Assunto , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata , Influenza Humana/imunologia , Células Matadoras Naturais/patologia , RNA-Seq , Análise de Célula Única , Fatores de Tempo , Fator de Crescimento Transformador beta/sangue , Carga Viral/imunologia , Replicação Viral/imunologiaRESUMO
Background: The immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adults, but it is still poorly investigated in the pediatric population. Methods: Of 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1-3.7) and 6.1 (5.3-7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR). Results: Overall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes. Conclusions: Adults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções Assintomáticas , Linfócitos B Reguladores/imunologia , COVID-19/patologia , Linfócitos T Reguladores/imunologia , Adulto , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Moléculas com Motivos Associados a Patógenos/sangue , Estudos Prospectivos , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Carga Viral/imunologiaRESUMO
Functional support-the availability of material aid, emotional support, or companionship-promotes general well-being. For men who have sex with men (MSM) living with HIV, having a person who supports you associates with viral suppression. This study examines the association between supportive partnerships and HIV viral suppression among middle-aged and aging MSM living with HIV. A total of 423 middle-aged and aging MSM (mean age, 58.2 years) from the Multicenter AIDS Cohort Study provided self-reported data about their partnerships. Separate Poisson regression models assessed how partnership type, support, strain, and duration from April 2017 were associated with repeated viral load measurements up to April 2019. Of the follow-up visits (N = 1289), 90.0% of participants were virally suppressed. Most participants reported being non-Hispanic White (61.0%) and college-educated (83.4%). Participants were asked about their primary partnerships (i.e., "someone they are committed to above anyone else") and secondary partnerships (i.e., those who can also be intimate or supportive but not necessarily romantic or sexual). The participants reported: no partnerships (45.2%), only primary partnerships (31.0%), only secondary partnerships (11.1%), or both primary and secondary partnerships (12.8%). Primary and secondary partnerships had mean (SD) durations of 15.9 (11.3) and 25.2 (16.5) years, respectively. Participants reporting both primary and secondary partnerships (compared with no partnership) showed significantly higher odds of being virally suppressed (adjusted prevalence ratio [aPR], 1.04; 95% CI, 1.00-1.08; p = 0.043). Albeit not statistically significant, primary-only (aPR, 1.01; 95% CI, 0.97-1.06; p = 0.547) or secondary-only (aPR, 1.03; 95% CI, 0.98-1.08; p = 0.224) partnership types were positively associated with viral suppression. Partner support and strain were not associated with viral suppression in any partnership group. Being older and non-Hispanic Black were positively and negatively associated with viral suppression, respectively. Encouraging partnerships should be considered one of clinicians' many tools to help middle-aged and aging MSM achieve long-term viral suppression.
Assuntos
Envelhecimento/imunologia , Infecções por HIV , Carga Viral/imunologia , Adulto , Idoso , Estudos de Coortes , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Homossexualidade Masculina/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Comportamento Sexual/psicologia , Parceiros Sexuais/psicologia , Minorias Sexuais e de Gênero/psicologiaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The continued spread of SARS-CoV-2 increases the probability of influenza/SARS-CoV-2 coinfection, which may result in severe disease. In this study, we examine the disease outcome of influenza A virus (IAV) and SARS-CoV-2 coinfection in K18-hACE2 mice. Our data indicate enhance susceptibility of IAV-infected mice to developing severe disease upon coinfection with SARS-CoV-2 two days later. In contrast to nonfatal influenza and lower mortality rates due to SARS-CoV-2 alone, this coinfection results in severe morbidity and nearly complete mortality. Coinfection is associated with elevated influenza viral loads in respiratory organs. Remarkably, prior immunity to influenza, but not to SARS-CoV-2, prevents severe disease and mortality. This protection is antibody-dependent. These data experimentally support the necessity of seasonal influenza vaccination for reducing the risk of severe influenza/COVID-19 comorbidity during the COVID-19 pandemic.
Assuntos
COVID-19/imunologia , COVID-19/virologia , Coinfecção/imunologia , Coinfecção/virologia , Imunidade , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Antivirais/imunologia , COVID-19/patologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/genética , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regulação para Cima/genética , Carga Viral/imunologiaRESUMO
BACKGROUND: Type III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown. METHODS: Using an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection. RESULTS: Surprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not. CONCLUSIONS: These data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.
Assuntos
Interferons/análise , Interferons/imunologia , Interleucinas/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Linhagem Celular , Coinfecção/imunologia , Coinfecção/microbiologia , Cães , Feminino , Interferons/genética , Interleucinas/genética , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/patologia , Polimorfismo Genético/genética , Infecções Estafilocócicas/prevenção & controle , Superinfecção/imunologia , Superinfecção/microbiologia , Carga Viral/imunologia , Interferon lambdaRESUMO
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.