RESUMO
BACKGROUND: Data are limited on the role of preinfection humoral immunity protection against Omicron BA.5 infection and long coronavirus disease (COVID) development. METHODS: We conducted nested case-control analysis among tertiary hospital staff in Tokyo who donated blood samples in June 2022 (1 month before Omicron BA.5 wave), approximately 6 months after receiving a third dose of COVID-19 mRNA vaccine. We measured live virus-neutralizing antibody titers against wild type and Omicron BA.5, and anti-receptor-binding domain (RBD) antibody titers at preinfection, and compared them between cases and propensity-matched controls. Among the breakthrough cases, we examined association between preinfection antibody titers and incidence of long COVID. RESULTS: Preinfection anti-RBD and neutralizing antibody titers were lower in cases than controls. Neutralizing titers against wild type and Omicron BA.5 were 64% (95% confidence interval [CI], 42%-77%) and 72% (95% CI, 53%-83%) lower, respectively, in cases than controls. Individuals with previous Omicron BA.1/BA.2 infections were more frequent among controls than cases (10.3% vs 0.8%), and their Omicron BA.5 neutralizing titers were 12.8-fold higher than infection-naive individuals. Among cases, preinfection antibody titers were not associated with incidence of long COVID. CONCLUSIONS: Preinfection immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a role in protecting against the Omicron BA.5 infection but not preventing long COVID.
Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , Humanos , Anticorpos Neutralizantes , Infecções Irruptivas , Vacinas contra COVID-19 , Pontuação de Propensão , SARS-CoV-2 , Anticorpos AntiviraisRESUMO
BACKGROUND: Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron. METHODS: Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups. RESULTS: Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. CONCLUSIONS: Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.
Assuntos
Anticorpos Neutralizantes , Epidemias , Humanos , Vacina BNT162 , Infecções Irruptivas , Vacinação , Anticorpos AntiviraisRESUMO
BACKGROUND: While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. METHODS: We describe incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected 3 matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the 2 groups. RESULTS: No COVID-19 cases occurred 1-2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2-4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and participants had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. CONCLUSIONS: Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant outbreak. The result points to the importance of infection-control measures in the post-vaccination era, irrespective of immunogenicity profile.
Assuntos
Anticorpos Neutralizantes , COVID-19 , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Pessoal de Saúde , Hospitais , Humanos , Encaminhamento e Consulta , SARS-CoV-2 , Tóquio/epidemiologia , VacinaçãoRESUMO
Hepatitis B virus (HBV) is a stealth virus that exhibits only minimal induction of the interferon system, which is required for both innate and adaptive immune responses. However, 90% of acutely infected adults can clear the virus, suggesting the presence of additional mechanisms that facilitate viral clearance. Here, we report that Maf bZIP transcription factor F (MafF) promotes host defense against infection with HBV. Using a small interfering RNA (siRNA) library and an HBV/NanoLuc (NL) reporter virus, we screened to identify anti-HBV host factors. Our data showed that silencing of MafF led to a 6-fold increase in luciferase activity after HBV/NL infection. Overexpression of MafF reduced HBV core promoter transcriptional activity, which was relieved upon mutation of the putative MafF binding region. Loss of MafF expression through CRISPR/Cas9 editing (in HepG2-hNTCP-C4 cells) or siRNA silencing (in primary hepatocytes [PXB cells]) induced HBV core RNA and HBV pregenomic RNA (pgRNA) levels, respectively, after HBV infection. MafF physically binds to the HBV core promoter and competitively inhibits HNF-4α binding to an overlapping sequence in the HBV enhancer II sequence (EnhII), as seen by chromatin immunoprecipitation (ChIP) analysis. MafF expression was induced by interleukin-1ß (IL-1ß) or tumor necrosis factor alpha (TNF-α) treatment in both HepG2 and PXB cells, in an NF-κB-dependent manner. Consistently, MafF expression levels were significantly enhanced and positively correlated with the levels of these cytokines in patients with chronic HBV infection, especially in the immune clearance phase. IMPORTANCE HBV is a leading cause of chronic liver diseases, infecting about 250 million people worldwide. HBV has developed strategies to escape interferon-dependent innate immune responses. Therefore, the identification of other anti-HBV mechanisms is important for understanding HBV pathogenesis and developing anti-HBV strategies. MafF was shown to suppress transcription from the HBV core promoter, leading to significant suppression of the HBV life cycle. Furthermore, MafF expression was induced in chronic HBV patients and in primary human hepatocytes (PXB cells). This induction correlated with the levels of inflammatory cytokines (IL-1ß and TNF-α). These data suggest that the induction of MafF contributes to the host's antiviral defense by suppressing transcription from selected viral promoters. Our data shed light on a novel role for MafF as an anti-HBV host restriction factor.
Assuntos
Hepatite B Crônica/patologia , Imunidade Inata/imunologia , Fator de Transcrição MafF/metabolismo , Proteínas Nucleares/metabolismo , Transcrição Gênica/genética , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Humanos , Interleucina-1beta/imunologia , Fator de Transcrição MafF/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND AND AIMS: Chronic HBV infection is a major health problem worldwide. Currently, the first-line treatment for HBV is nucleos(t)ide analogs or interferons; however, efficient therapeutic approaches that enable cure are lacking. Therefore, anti-HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function. APPROACH AND RESULTS: In this study, we investigated the inhibitory effect of bile acid (BA) derivatives-namely obeticholic acid (OCA), 6α-ethyl-24-nor-5ß-cholane-3α,7α,23-triol-23 sulfate sodium salt (INT-767; a dual agonist of FXR and Takeda G protein-coupled receptor [TGR5]), and 6α-ethyl-23(S)-methyl-cholic acid (INT-777; a TGR5 agonist)-3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064; a FXR agonist), cyclosporin A, and irbesartan. OCA and INT-777 suppressed HBV infection in HepG2-human NTCP-C4 cells. Interestingly, INT-767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT-767 was stronger than various natural BAs. Furthermore, in chimeric mice with humanized liver, INT-767 markedly delayed the initial rise of HBsAg, HBeAg, and HBV DNA and reduced covalently closed circular DNA. The strong inhibitory effect of INT-767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the postentry step. CONCLUSIONS: Our results suggest that BA derivatives, particularly INT-767, are prospective candidate anti-HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of anti-HBV agents.
Assuntos
Antivirais/farmacologia , Hepatite B Crônica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas G/agonistas , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Ácidos e Sais Biliares/farmacologia , Ácidos e Sais Biliares/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Ácidos Cólicos/farmacologia , Ácidos Cólicos/uso terapêutico , Modelos Animais de Doenças , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/virologia , Humanos , Masculino , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Estudos Prospectivos , Receptores Citoplasmáticos e Nucleares/metabolismo , Simportadores/metabolismo , Quimeras de TransplanteRESUMO
Vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy in preventing the onset of disease. However, the immune response to infection immediately after the first vaccination remains unknown. We examined the anti-SARS-CoV-2-binding-antibody titers and neutralizing activity in patients who developed coronavirus disease 2019 after the first vaccination. The amount of anti-SARS-CoV-2-binding antibodies and neutralizing activity drastically increased from the first to the second collection. Our results may provide important data on the course of immune response following vaccination.
Assuntos
COVID-19 , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Humanos , Testes de Neutralização/métodos , SARS-CoV-2 , VacinaçãoRESUMO
Management of COVID-19 patients with humoral immunodeficiency is challenging. We describe a woman with COVID-19 with multiple relapses due to anti-CD20 monoclonal antibody treatment. She was successfully treated with casirivimab/imdevimab and confirmed to have neutralizing antibodies. This case suggests that monoclonal antibodies have therapeutic and prophylactic value in patients with humoral immunodeficiency.
Assuntos
Antineoplásicos Imunológicos , Tratamento Farmacológico da COVID-19 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/uso terapêutico , Feminino , Humanos , SARS-CoV-2RESUMO
The Omicron variant of severe acute respiratory syndrome coronavirus 2 has multiple amino acid mutations in its spike proteins, which may allow it to evade immunity elicited by vaccination. We examined the neutralising activity and S1-IgG titres in patients with breakthrough infections caused by the Omicron variant after two doses of vaccination. We found that neutralising activity was significantly lower for the Omicron variant than for the Wuhan strain. Two doses of vaccination might not induce sufficient neutralising activity for the Omicron variant.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Humanos , Japão , SARS-CoV-2/genéticaRESUMO
Hepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates, from fish to human. Hepadnaviruses and their hosts have a long history of acquiring adaptive mutations. However, there are no reports providing direct molecular evidence for such a coevolutionary "arms race" between hepadnaviruses and their hosts. Here, we present evidence suggesting that the adaptive evolution of the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, has been influenced by virus infection. Evolutionary analysis of the NTCP-encoding genes from 20 mammals showed that most NTCP residues are highly conserved among species, exhibiting evolution under negative selection (dN/dS ratio [ratio of nonsynonymous to synonymous evolutionary changes] of <1); this observation implies that the evolution of NTCP is restricted by maintaining its original protein function. However, 0.7% of NTCP amino acid residues exhibit rapid evolution under positive selection (dN/dS ratio of >1). Notably, a substitution at amino acid (aa) 158, a positively selected residue, converting the human NTCP to a monkey-type sequence abrogated the capacity to support HBV infection; conversely, a substitution at this residue converting the monkey Ntcp to the human sequence was sufficient to confer HBV susceptibility. Together, these observations suggested a close association of the aa 158 positive selection with the pressure by virus infection. Moreover, the aa 158 sequence determined attachment of the HBV envelope protein to the host cell, demonstrating the mechanism whereby HBV infection would create positive selection at this NTCP residue. In summary, we provide the first evidence in agreement with the function of hepadnavirus as a driver for inducing adaptive mutation in host receptor.IMPORTANCE HBV and its hepadnavirus relatives infect a wide range of vertebrates, with a long infectious history (hundreds of millions of years). Such a long history generally allows adaptive mutations in hosts to escape from infection while simultaneously allowing adaptive mutations in viruses to overcome host barriers. However, there is no published molecular evidence for such a coevolutionary arms race between hepadnaviruses and hosts. In the present study, we performed coevolutionary phylogenetic analysis between hepadnaviruses and the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, combined with virological experimental assays for investigating the biological significance of NTCP sequence variation. Our data provide the first molecular evidence supporting that HBV-related hepadnaviruses drive adaptive evolution in the NTCP sequence, including a mechanistic explanation of how NTCP mutations determine host viral susceptibility. Our novel insights enhance our understanding of how hepadnaviruses evolved with their hosts, permitting the acquisition of strong species specificity.
Assuntos
Vírus da Hepatite B/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Receptores Virais/genética , Simportadores/genética , Proteínas do Envelope Viral/genética , Ligação Viral , Internalização do Vírus , Substituição de Aminoácidos/genética , Linhagem Celular Tumoral , Evolução Molecular , Células Hep G2 , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/crescimento & desenvolvimento , Humanos , Filogenia , Especificidade da Espécie , Proteínas do Envelope Viral/metabolismoRESUMO
Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, originated from simian immunodeficiency virus from chimpanzees (SIVcpz), the precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz strains (MB897, EK505, and MT145), four pandemic HIV-1 strains (NL4-3, NLCSFV3, JRCSF, and AD8), and two nonpandemic HIV-1 strains (YBF30 and DJO0131). Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a peak viral load comparable to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strain EK505 or MT145 as well as nonpandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is preadapted to humans, unlike the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation in env, a G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in both in vitro cell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1.IMPORTANCE From the mid-20th century, humans have been exposed to the menace of infectious viral diseases, such as severe acute respiratory syndrome coronavirus, Ebola virus, and Zika virus. These outbreaks of emerging/reemerging viruses can be triggered by cross-species viral transmission from wild animals to humans, or zoonoses. HIV-1, the causative agent of AIDS, emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzees, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. Here, by using a hematopoietic stem cell-transplanted humanized-mouse model, we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, preadapted to infect humans over other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.
Assuntos
Evolução Molecular , HIV-1/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Zoonoses/transmissão , Animais , Animais Selvagens/virologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Pan troglodytes/virologia , Filogenia , RNA Viral/genética , Carga Viral , Replicação ViralRESUMO
The interplay between viral and host proteins has been well studied to elucidate virus-host interactions and their relevance to virulence. Mammalian genes encode apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins, which act as intrinsic restriction factors against lentiviruses. To overcome APOBEC3-mediated antiviral actions, lentiviruses have evolutionarily acquired an accessory protein, viral infectivity factor (Vif), and Vif degrades host APOBEC3 proteins via a ubiquitin/proteasome-dependent pathway. Although the Vif-APOBEC3 interaction and its evolutionary significance, particularly those of primate lentiviruses (including HIV) and primates (including humans), have been well investigated, those of nonprimate lentiviruses and nonprimates are poorly understood. Moreover, the factors that determine lentiviral pathogenicity remain unclear. Here, we focus on feline immunodeficiency virus (FIV), a pathogenic lentivirus in domestic cats, and the interaction between FIV Vif and feline APOBEC3 in terms of viral virulence and evolution. We reveal the significantly reduced diversity of FIV subtype B compared to that of other subtypes, which may associate with the low pathogenicity of this subtype. We also demonstrate that FIV subtype B Vif is less active with regard to feline APOBEC3 degradation. More intriguingly, we further reveal that FIV protease cleaves feline APOBEC3 in released virions. Taken together, our findings provide evidence that a lentivirus encodes two types of anti-APOBEC3 factors, Vif and viral protease.IMPORTANCE During the history of mammalian evolution, mammals coevolved with retroviruses, including lentiviruses. All pathogenic lentiviruses, excluding equine infectious anemia virus, have acquired the vif gene via evolution to combat APOBEC3 proteins, which are intrinsic restriction factors against exogenous lentiviruses. Here we demonstrate that FIV, a pathogenic lentivirus in domestic cats, antagonizes feline APOBEC3 proteins by both Vif and a viral protease. Furthermore, the Vif proteins of an FIV subtype (subtype B) have attenuated their anti-APOBEC3 activity through evolution. Our findings can be a clue to elucidate the complicated evolutionary processes by which lentiviruses adapt to mammals.
Assuntos
Desaminases APOBEC/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Produtos do Gene vif/metabolismo , Vírus da Imunodeficiência Felina/genética , Desaminases APOBEC/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Gatos , Evolução Molecular , Produtos do Gene vif/genética , Interações Hospedeiro-Patógeno , Vírus da Imunodeficiência Felina/metabolismo , Vírus da Imunodeficiência Felina/patogenicidade , VirulênciaRESUMO
BACKGROUND & AIMS: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. METHODS: We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. RESULTS: We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC50. Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. CONCLUSIONS: This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. LAY SUMMARY: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.
Assuntos
Ciclosporinas/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus/efeitos dos fármacos , Antivirais/efeitos adversos , Antivirais/farmacologia , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Ciclosporinas/efeitos adversos , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Vírus Delta da Hepatite/efeitos dos fármacos , Vírus Delta da Hepatite/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , HumanosRESUMO
BACKGROUND: Sarcoidosis is a systemic disease of unknown etiology, in which granulomas develop in various organs, including the skin, lungs, eyes, or heart. It has been reported that patients with sarcoidosis are more likely to develop panic disorder than members of the general population. However, there are many unknown factors concerning the causal relationship between these conditions. CASE PRESENTATION: We present the case of a 57-year-old woman who appeared to have panic disorder, as she experienced repeated panic attacks induced by transient complete atrioventricular block, associated with cardiac sarcoidosis. Psychotherapy and pharmacotherapy were not effective in the treatment of her panic attacks. However, when we implanted a permanent pacemaker and initiated steroid treatment for cardiac sarcoidosis, panic attacks were ameliorated. Based on these findings, we diagnosed the patient's symptoms as an anxiety disorder associated with cardiac sarcoidosis, rather than panic disorder. CONCLUSIONS: This report highlights the importance of considering cardiac sarcoidosis in the differential diagnosis of panic disorder. This cardiac disease should be considered especially in patients have a history of cardiac disease (e.g., arrhythmia) and atypical presentations of panic symptoms. Panic disorder is a psychiatric condition that is typically diagnosed after other medical conditions have been excluded. Because the diagnosis of sarcoidosis is difficult in some patients, caution is required. The palpitations and symptoms of heart failure associated with cardiac sarcoidosis can be misdiagnosed as psychiatric symptoms of panic disorder. The condition described in the current case study appears to constitute a physical disease, the diagnosis of which requires significant consideration and caution.
Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/psicologia , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/psicologia , Sarcoidose/diagnóstico , Sarcoidose/psicologia , Cardiomiopatias/fisiopatologia , Diagnóstico Diferencial , Erros de Diagnóstico , Eletrocardiografia/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Transtorno de Pânico/fisiopatologia , Sarcoidose/fisiopatologiaRESUMO
Several APOBEC3 proteins, particularly APOBEC3D, APOBEC3F, and APOBEC3G, induce G-to-A hypermutations in HIV-1 genome, and abrogate viral replication in experimental systems, but their relative contributions to controlling viral replication and viral genetic variation in vivo have not been elucidated. On the other hand, an HIV-1-encoded protein, Vif, can degrade these APOBEC3 proteins via a ubiquitin/proteasome pathway. Although APOBEC3 proteins have been widely considered as potent restriction factors against HIV-1, it remains unclear which endogenous APOBEC3 protein(s) affect HIV-1 propagation in vivo. Here we use a humanized mouse model and HIV-1 with mutations in Vif motifs that are responsible for specific APOBEC3 interactions, DRMR/AAAA (4A) or YRHHY/AAAAA (5A), and demonstrate that endogenous APOBEC3D/F and APOBEC3G exert strong anti-HIV-1 activity in vivo. We also show that the growth kinetics of 4A HIV-1 negatively correlated with the expression level of APOBEC3F. Moreover, single genome sequencing analyses of viral RNA in plasma of infected mice reveal that 4A HIV-1 is specifically and significantly diversified. Furthermore, a mutated virus that is capable of using both CCR5 and CXCR4 as entry coreceptor is specifically detected in 4A HIV-1-infected mice. Taken together, our results demonstrate that APOBEC3D/F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3D and APOBEC3F are capable of promoting viral diversification and evolution in vivo.
Assuntos
Citidina Desaminase/metabolismo , Citosina Desaminase/metabolismo , HIV-1 , Mutação/genética , RNA Viral/genética , Animais , Evolução Biológica , Mapeamento Cromossômico , Modelos Animais de Doenças , Variação Genética/genética , Humanos , Camundongos , Receptores CXCR4/genética , Replicação Viral/fisiologiaRESUMO
In the present case, the subject was a 31-year-old woman with obesophobia who restricted her energy intake and repeatedly induced vomiting and misused laxatives after binge eating, which caused a sudden weight loss of 29 kg in approximately 5 months. In January 20XX, the subject was first examined as an outpatient at our psychiatric department at the recommendation of her eldest son. Upon diagnosis of anorexia nervosa, the subject underwent outpatient treatment ; however, there was no improvement in the disturbance in self-per- ceived weight or shape, and the subject voiced her desire to lose weight. In May 20XX, the subject complained of chest pain, pharyngeal pain, and respiratory distress after self-induced vomiting and was, thus, examined at the psychiatric outpatient services. Chest X-ray and chest CT revealed pneumomediastinum and subcutaneous emphysema. Spontaneous oesophageal rupture, a fatal condition, was suspected and, therefore, the subject was transferred to a more advanced medical institution capable of esophageal surgery. After admission, spontane- ous oesophageal rupture was ruled out based on the results of upper gastrointestinal endos- copy with esophagography, and spontaneous pneumomediastinum was diagnosed. The pneu- momediastinum disappeared with conservative treatment ; however, after approximately 8 months, spontaneous pneumomediastinum recurred, following self-induced vomiting. For patients with eating disorders and who are involved in self-induce vomiting, we believe that the vomiting can cause pneumomediastinum, and it is assumed that continuation or recommencement of vomiting can potentially increase the risk that pneumomediastinum will recur. We, therefore, report recurring pneumoediastinum as a physical complication caused by self- induced vomiting that should be noted in clinical practice of the psychiatric department.
Assuntos
Anorexia Nervosa/complicações , Enfisema Mediastínico/complicações , Adulto , Feminino , Humanos , RecidivaRESUMO
APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3) proteins are cellular DNA deaminases that restrict a broad spectrum of lentiviruses. This process is counteracted by Vif (viral infectivity factor) of lentiviruses, which binds APOBEC3s and promotes their degradation. CBF-ß (core binding factor subunit ß) is an essential co-factor for the function of human immunodeficiency virus type 1 Vif to degrade human APOBEC3s. However, the requirement for CBF-ß in Vif-mediated degradation of other mammalian APOBEC3 proteins is less clear. Here, we determined the sequence of feline CBFB and performed phylogenetic analyses. These analyses revealed that mammalian CBFB is under purifying selection. Moreover, we demonstrated that CBF-ß is dispensable for feline immunodeficiency virus Vif-mediated degradation of APOBEC3s of its host. These findings suggested that primate lentiviruses have adapted to use CBF-ß, an evolutionary stable protein, to counteract APOBEC3 proteins of their hosts after diverging from other lentiviruses.
Assuntos
Subunidade beta de Fator de Ligação ao Core/metabolismo , Citidina Desaminase/metabolismo , HIV-1/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Desaminases APOBEC , Animais , Gatos , Linhagem Celular , Citosina Desaminase/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , FilogeniaRESUMO
APOBEC3F and APOBEC3G cytidine deaminases potently inhibit human immunodeficiency virus type 1 (HIV-1) replication by enzymatically inserting G-to-A mutations in viral DNA and/or impairing viral reverse transcription independently of their deaminase activity. Through experimental and mathematical investigation, here we quantitatively demonstrate that 99.3% of the antiviral effect of APOBEC3G is dependent on its deaminase activity, whereas 30.2% of the antiviral effect of APOBEC3F is attributed to deaminase-independent ability. This is the first report quantitatively elucidating how APOBEC3F and APOBEC3G differ in their anti-HIV-1 modes.
Assuntos
Citidina Desaminase/metabolismo , Citosina Desaminase/metabolismo , HIV-1/imunologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Replicação Viral , Desaminase APOBEC-3G , Linhagem Celular , Humanos , Modelos TeóricosRESUMO
The LAMPdirect Genelyzer KIT allows for the detection of SARS-CoV-2 RNA in saliva samples with a loop-mediated isothermal amplification (LAMP) method and generates results within 20 min. It has been approved by the Pharmaceuticals and Medical Devices Agency in Japan. In this study, the performance of the LAMPdirect Genelyzer KIT was compared with that of the RT-qPCR reference method using 50 nasopharyngeal swabs and 100 saliva samples. In addition, we evaluated the applicability of an alternative reverse transcriptase and the effects of an inactivation buffer. The total agreement rates were 80.0 % and 82.0 % for nasopharyngeal and saliva samples, respectively. When considering samples at the detection limit (50 copies/reaction) that increases the chance of transmission between humans, the total agreement rates were 100% and 94.1% for nasopharyngeal and saliva samples, respectively. The LAMP method is simple, fast, and inexpensive, making it useful for small medical institutions or rural areas.
Assuntos
COVID-19 , Técnicas de Diagnóstico Molecular , Nasofaringe , Técnicas de Amplificação de Ácido Nucleico , RNA Viral , SARS-CoV-2 , Saliva , Humanos , Saliva/virologia , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Nasofaringe/virologia , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/genética , RNA Viral/isolamento & purificação , COVID-19/diagnóstico , COVID-19/virologia , Técnicas de Diagnóstico Molecular/métodos , Sensibilidade e Especificidade , Kit de Reagentes para Diagnóstico/normas , Teste de Ácido Nucleico para COVID-19/métodos , Teste de Ácido Nucleico para COVID-19/instrumentação , Manejo de Espécimes/métodosRESUMO
Delays in clearance and rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in immunocompromised patients. We encountered a case of recurrent, multi-mutational SARS-CoV-2 infection in a 40-year-old man with severe immunodeficiency due to Good syndrome. The patient had not received the SARS-CoV-2 vaccination. In August 2021, he was first admitted to the hospital owing to coronavirus disease 2019 (COVID-19) pneumonia and was administered dexamethasone, remdesivir, and baricitinib. Although his fever and respiratory condition improved once, chest computed tomography (CT) revealed extensive diffuse consolidation and ground-glass opacities (GGOs), and both methylprednisolone pulse therapy and tocilizumab yielded a limited effect. After a third course of remdesivir without immunosuppressants or steroids, the patient recovered, and he tested negative for SARS-CoV-2. On day 272 since the clinical onset, he was readmitted with dyspnea and mild fever due to a COVID-19 recurrence. He was infected with the Delta variant (AY.29), despite the Omicron (BA.2) variant being predominant at that time. During this admission, additional remdesivir and casirivimab/imdevimab yielded marked effects, and the SARS-CoV-2 quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) tests rapidly returned negative. Phylogenetic analysis demonstrated the accumulation of mutations, including those yielding remdesivir resistance, throughout the SARS-CoV-2 genome. Appropriate use of antivirals and monoclonal antibodies may aid in the recovery of patients with COVID-19 and immunodeficiency and in preventing the emergence of multi-mutational SARS-CoV-2 variants.