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1.
Immunity ; 55(2): 341-354.e7, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34990590

RESUMO

The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%-5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.


Assuntos
Anticorpos Amplamente Neutralizantes/genética , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/genética , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/química , Anticorpos Amplamente Neutralizantes/imunologia , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Epitopos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/imunologia , Anticorpos Anti-Hepatite C/química , Anticorpos Anti-Hepatite C/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia
2.
Transpl Infect Dis ; 26(1): e14233, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38180168

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug-induced side effects and dose reduction due to decline in kidney function. METHOD: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections. RESULTS: In the studied cohort, 18.7% of patients showed a high-risk (HR) constellation (D+/R-) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients. CONCLUSION: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post-KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , Citomegalovirus , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Viremia/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/prevenção & controle , Valganciclovir/uso terapêutico , Transplantados , Ganciclovir/uso terapêutico , Ganciclovir/farmacologia
3.
HIV Med ; 24(7): 785-793, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36883641

RESUMO

OBJECTIVES: Our objective was to assess immune responses and their influencing factors in people living with HIV after messenger RNA (mRNA)-based COVID-19 booster vaccination (third dose). METHODS: This was a retrospective cohort study of people living with HIV who received booster vaccination with BNT-162b2 or mRNA-1273 between October 2021 and January 2022. We assessed anti-spike receptor-binding domain (RBD) immunoglobulin G (IgG), virus neutralizing activity (VNA) titres reported as 100% inhibitory dilution (ID100 ), and T-cell response (using interferon-gamma-release-assay [IGRA]) at baseline and quarterly follow-up visits. Patients with reported COVID-19 during follow-up were excluded. Predictors of serological immune response were analyzed using multivariate regression models. RESULTS: Of 84 people living with HIV who received an mRNA-based booster vaccination, 76 were eligible for analysis. Participants were on effective antiretroviral therapy (ART) and had a median of 670 CD4+ cells/µL (interquartile range [IQR] 540-850). Following booster vaccination, median anti-spike RBD IgG increased by 705.2 binding antibody units per millilitre (BAU/mL) and median VNA titres increased by 1000 ID100 at the follow-up assessment (median 13 weeks later). Multivariate regression revealed that time since second vaccination was a predictor of stronger serological responses (p < 0.0001). No association was found for other factors, including CD4+ status, choice of mRNA vaccine, or concomitant influenza vaccination. In total, 45 patients (59%) had a reactive baseline IGRA, of whom two lost reactivity during follow-up. Of 31 patients (41%) with non-reactive baseline IGRA, 17 (55%) converted to reactive and seven (23%) remained unchanged following booster vaccination. CONCLUSIONS: People living with HIV with ≥500 CD4+ cells/µL showed favourable immune responses to mRNA-based COVID-19 booster vaccination. A longer time (up to 29 weeks) since second vaccination was associated with higher serological responses, whereas choice of mRNA vaccine or concomitant influenza vaccination had no impact.


Assuntos
COVID-19 , Infecções por HIV , Influenza Humana , Humanos , Estudos Retrospectivos , COVID-19/prevenção & controle , Vacinação , RNA Mensageiro , Imunidade , Imunoglobulina G , Anticorpos Antivirais
4.
Eur J Haematol ; 111(6): 963-969, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37772680

RESUMO

BACKGROUND: Immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) decisively influences the occurrence of opportunistic infections, one of the leading causes of death among this group of patients. Yet, today, there are no laboratory parameters mirroring immune function sufficiently. Torque teno virus (TTV) has already proven itself as a functional immune marker in other settings. AIMS: In this analysis, we investigated whether monitoring of TTV-DNA load in whole blood is able to provide additional information on the capacity of the immune system to control cytomegalovirus (CMV) replication in allo-HSCT recipients. METHODS: Whole blood samples from 59 patients were collected upon allo-HSCT (between Day -7 and +10), on Day +14, +21, +28, +56, +90, and +365 post-transplant. TTV-DNA loads and other relevant clinical information were correlated with the risk of CMV infections or reactivations, defined by evidence of viral replication in blood. RESULTS: CMV serostatus of the recipient and a TTV load below 1000 copies/mL upon allo-HSCT were significantly associated with an increased incidence of CMV infection or reactivation. CONCLUSIONS: Quantification of TTV load in the early phase of allo-HSCT procedure could provide additional information in order to identify patients at risk for CMV infection or reactivation.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Torque teno virus , Humanos , Citomegalovirus , Torque teno virus/genética , DNA Viral , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Medição de Risco , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Carga Viral
5.
Infection ; 51(2): 459-464, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35759174

RESUMO

PURPOSE: School closures have been used as part of lockdown strategies to contain the spread of SARS-CoV-2, adversely affecting children's health and education. To ensure the accessibility of educational institutions without exposing society to the risk of increased transmissions, it is essential to establish SARS-CoV-2 testing strategies that are child-friendly, scalable and implementable in a daily school routine. Self-sampling using non-invasive saliva swabs combined with pooled RT-qPCR testing (Lolli-Method) has been proven to be a sensitive method for the detection of SARS-CoV-2. METHODS: We conducted a pilot project in Cologne, Germany, designed to determine the feasibility of a large-scale rollout of the Lolli-Method for testing without any additional on-site medical staff in schools. Over a period of three weeks, students from 22 schools were sampled using the Lolli-Method. At the end of the project, teachers were asked to evaluate the overall acceptance of the project. RESULTS: We analyzed a total of 757 pooled RT-qPCRs obtained from 8,287 individual swabs and detected 7 SARS-CoV-2 infected individuals. The Lolli-Method was shown to be a feasible and accepted testing strategy whose application is only slightly disruptive to the daily school routine. CONCLUSION: Our observations suggest that the Lolli-Method in combination with pooled RT-qPCR can be implemented for SARS-CoV-2 surveillance in daily school routine, applicable on a large scale.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Projetos Piloto , SARS-CoV-2/genética , Teste para COVID-19 , COVID-19/diagnóstico , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Instituições Acadêmicas
6.
HIV Med ; 23(2): 159-168, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34622550

RESUMO

BACKGROUND: As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia. METHODS: HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application. RESULTS: Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/µL and median (IQR) HIV-1 viral load was 30 220 (7963-82 598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected. CONCLUSIONS: We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Etiópia/epidemiologia , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Ritonavir/uso terapêutico , Carga Viral
7.
Emerg Infect Dis ; 26(10): 2439-2443, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946725

RESUMO

We analyzed 1,397 HIV-1 pol sequences of antiretroviral therapy-naive patients in a total of 7 university hospitals in Bonn, Cologne, Frankfurt, Hamburg, Hannover, and Munich, Germany. Phylogenetic and network analysis elucidated numerous cases of shared drug resistance mutations among genetically linked patients; K103N was the most frequently shared mutation.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Genótipo , Alemanha/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Mutação , Filogenia
8.
Nucleic Acids Res ; 46(W1): W271-W277, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29718426

RESUMO

Identifying resistance to antiretroviral drugs is crucial for ensuring the successful treatment of patients infected with viruses such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV). In contrast to Sanger sequencing, next-generation sequencing (NGS) can detect resistance mutations in minority populations. Thus, genotypic resistance testing based on NGS data can offer novel, treatment-relevant insights. Since existing web services for analyzing resistance in NGS samples are subject to long processing times and follow strictly rules-based approaches, we developed geno2pheno[ngs-freq], a web service for rapidly identifying drug resistance in HIV-1 and HCV samples. By relying on frequency files that provide the read counts of nucleotides or codons along a viral genome, the time-intensive step of processing raw NGS data is eliminated. Once a frequency file has been uploaded, consensus sequences are generated for a set of user-defined prevalence cutoffs, such that the constructed sequences contain only those nucleotides whose codon prevalence exceeds a given cutoff. After locally aligning the sequences to a set of references, resistance is predicted using the well-established approaches of geno2pheno[resistance] and geno2pheno[hcv]. geno2pheno[ngs-freq] can assist clinical decision making by enabling users to explore resistance in viral populations with different abundances and is freely available at http://ngs.geno2pheno.org.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Software , Genoma Viral/genética , Genótipo , Infecções por HIV/genética , Infecções por HIV/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
9.
Clin Infect Dis ; 68(9): 1539-1546, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30169606

RESUMO

BACKGROUND: Geographical allocation of interventions focusing on hotspots of human immunodeficiency virus (HIV) transmission has the potential to improve efficiency. We used phylogeographic analyses to identify hotspots of the HIV transmission in Cologne-Bonn, Germany. METHODS: We included 714 HIV-1 infected individuals, followed up at the University Hospitals Cologne and Bonn. Distance-based molecular network analyses were performed to infer putative relationships. Characteristics of genetically linked individuals and assortativity (shared characteristics) were analyzed. Geospatial diffusion (ie, viral gene flow) was evaluated using a Slatkin-Maddison approach. Geospatial dispersal was determined by calculating the average distance between the residences of linked individuals (centroids of 3-digit zip code). RESULTS: In sum, 217/714 (30.4%) sequences had a putative genetic linkage, forming 77 clusters (size range: 2-8). Linked individuals were more likely to live in areas surrounding the city center (P = .043), <30 years of age (P = .009). and infected with HIV-1 subtype B (P = .002). Clustering individuals were nonassortative by area of residency (-.0026, P = .046). Geospatial analyses revealed a median distance between genetically linked individuals of 23.4 kilometers (km), lower than expected (P < .001). Slatkin-Maddison analyses revealed increased gene flow from central Cologne toward the surrounding areas (P < .001). CONCLUSION: Phylogeographic analysis suggests that central Cologne may be a significant driver of the regional epidemic. Although clustering individuals lived closer than unlinked individuals, they were less likely to be linked to others from their same zip code. These results could help public health entities better understand transmission dynamics, facilitating allocation of resources to areas of greatest need.


Assuntos
Epidemias , Genes pol , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , HIV-1/genética , Família Multigênica , Adulto , Feminino , Fluxo Gênico , Ligação Genética , Alemanha/epidemiologia , Infecções por HIV/virologia , HIV-1/classificação , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Filogeografia , Saúde Pública/estatística & dados numéricos , Estudos Retrospectivos , Análise de Sequência de RNA , Análise Espaço-Temporal , Viagem/estatística & dados numéricos
11.
Med Microbiol Immunol ; 206(5): 355-362, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28702856

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for several hematological diseases. However, the first year post-transplantation is often complicated by infections and graft-versus-host disease (GVHD). Improvements in immunological monitoring could reduce such post-transplant complications. Torque Teno virus (TTV), a chronically persisting DNA virus, is reported to be a marker for immune function in immunocompromised patients. In the present study, the TTV kinetics were analyzed to investigate the potential role of TTV viremia as immune-competence read-out after allo-HSCT. Twenty-three monocentric allo-HSCT recipients were retrospectively tested for TTV-DNA in whole blood at given day post-transplant. Dynamics of TTV viremia was analyzed with respect to episodes of non-TTV viral reactivations (CMV, EBV, and BKPyV), acute GVHD, and recovery of immune cells. Recipients affected by persisting viral infections and/or GVHD during the first 100 days after allo-HSCT showed a significantly higher median TTV load at day +30 than patients with a less complicated clinical course (p = 0.005). This was also associated with a total lymphocyte count <5.5E+08 cells/L in this high-risk group (p = 0.039). These findings suggest that TTV could represent an additional parameter to identify patients at higher risk for complications in the first 100 days following allo-HSCT. Prospective studies, including the monitoring of lymphocyte subsets, are required to define the potential use of TTV in immunological monitoring after allo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Torque teno virus/isolamento & purificação , Transplante Homólogo/efeitos adversos , Carga Viral , Viroses/epidemiologia , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Viroses/diagnóstico
12.
Eur J Haematol ; 99(2): 133-140, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28401591

RESUMO

OBJECTIVES: Aim of this retrospective study was to analyze the dynamics of BKPyV reactivation in allogeneic hematopoietic stem cell transplant recipients in order to identify patients with higher risk to develop BKPyV-associated hemorrhagic cystitis (BKPyV-associated HC). METHODS: The study included 58 allo-HSCT recipients from the University Hospital of Cologne detected BKPyV positive by real-time PCR between 2009 and 2015. For correlative analysis, the first detected BKPyV-DNA load in urine and in plasma as well as the onset and severity of HC following the first day of conditioning regimen was considered. Phylogenetic analysis of BKPyV isolates was performed. RESULTS: In 25 of 58 patients, BKPyV-DNA was detected in urine only (group U), whereas 33 patients developed additional viremia (group P). A chronologic sequence viruria-viremia-HC was identified. Viral load of >106 copies/mL at first viruria and evidence of viremia after 45 days from the start of conditioning represented risk factors for the onset of HC. Molecular characterization revealed a non-stereotypic distribution of viral subtypes across groups U and P. CONCLUSIONS: Monitoring of BKPyV-DNA by real-time PCR after initiation of conditioning, regularly performed in clinical practice, can be a crucial tool for the early identification of patients with higher risk of BKPyV-associated HC.


Assuntos
Cistite/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/etiologia , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/virologia , Polyomavirus/fisiologia , Ativação Viral , Adulto , Idoso , Cistite/diagnóstico , DNA Viral , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Hemorragia/diagnóstico , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Filogenia , Polyomavirus/classificação , Infecções por Polyomavirus/diagnóstico , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Carga Viral , Latência Viral , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 110(41): 16538-43, 2013 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-24043801

RESUMO

Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.


Assuntos
Antirretrovirais/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Imunoterapia/métodos , Animais , Antirretrovirais/farmacologia , Anticorpos Neutralizantes/farmacologia , Primers do DNA/genética , DNA Viral/metabolismo , Dependovirus , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Carga Viral/efeitos dos fármacos
14.
Med Microbiol Immunol ; 204(5): 613-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25678083

RESUMO

Progressive multifocal leukoencephalopathy (PML) represents a rare but potentially fatal reactivation of JC-polyomavirus (JCPyV) recently also reported in patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA) treated with rituximab. The aim of the present study was to analyse the pattern of JCPyV infections in patients with RA undergoing treatment with biologic agents. Urine and blood samples were analysed from 80 patients for antibody levels and/or the presence of JCPyV DNA. Genotyping of the control region and VP1 was performed for all JCPyV DNA-positive specimens. Viremia of JCPyV was only temporarily detected in two patients, and these viruses did not carry any mutations associated with the occurrence of PML. JCPyV DNA was prevalent in initial urine samples of 33% of all patients. RA patients who have consecutively been treated with two or more biologic agents revealed significantly higher prevalence of JCPyV DNA in the urine compared to RA patients treated with their first biologic agent. The presence of JCPyV DNA in the urine closely correlated to JCPyV antibody positivity, and therefore, antibody titres were higher in RA patients who had consecutively received two or more biologic agents over time. Therefore, the overall number of biologic agents had an impact on the pattern of JCPyV detection in this study. Hence, JCPyV antibody screening might be useful as part of the PML risk stratification for RA patients in the future.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Rituximab/uso terapêutico , Adulto , Idoso , Anticorpos Antivirais/sangue , Sangue/virologia , DNA Viral/sangue , DNA Viral/urina , Feminino , Genótipo , Humanos , Fatores Imunológicos/efeitos adversos , Vírus JC/classificação , Vírus JC/genética , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/efeitos adversos , Urina/virologia
15.
Intervirology ; 58(3): 184-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26139571

RESUMO

BACKGROUND: Resistance analysis from viral RNA is restricted to detectable viral load. Therefore, analysis from proviral DNA could help in cases with low-level or suppressed viremia. METHODS: Viral plasma RNA and the corresponding cellular proviral DNA of 78 EDTA samples from 48 therapy-naïve (TN) and 30 therapy-experienced (TE) HIV-1-infected patients were isolated and analyzed for their resistance profiles in the protease and reverse transcriptase genes. RESULTS: Overall, 175 drug-resistance mutations (DRMs) were detected in 25/30 TE (83.3%) and 5/48 TN (10.4%) samples. The TE patients displayed a mean number of 6.68 DRMs in RNA and 5.20 in DNA. In the TN patients, a mean of 0.8 DRMs was found in RNA and 1.0 in DNA; 75% of the DRMs were detected in RNA and DNA simultaneously. In the TE samples, 76% of the DRMs were detected simultaneously in RNA and DNA, 23% exclusively in RNA and 1% in DNA only. The TN samples revealed a significantly higher frequency of DRMs in DNA than in RNA. CONCLUSIONS: Proviral DNA resistance testing provides additional resistance information for TN patients. It is also a reliable alternative for TE patients with unsuccessful RNA testing and can provide valuable information when no records are available.


Assuntos
Fármacos Anti-HIV/farmacologia , DNA Viral/genética , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Provírus/genética , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Provírus/efeitos dos fármacos , Provírus/isolamento & purificação , RNA Viral/sangue , RNA Viral/isolamento & purificação , DNA Polimerase Dirigida por RNA/genética , Carga Viral , Viremia/tratamento farmacológico
16.
Viruses ; 15(7)2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37515133

RESUMO

Resistance to multiple antiretroviral drugs among people living with HIV (PLWH) can result in a high pill burden, causing toxicity and drug interactions. Thus, the goal is to simplify treatment regimens while maintaining effectiveness. However, former resistance analysis data may not be current or complete. The use of proviral DNA genotyping may assist in selecting appropriate treatment options. A retrospective study was carried out on individuals belonging to the Cologne HIV cohort with a resistance history to two or more antiretroviral (ARV) classes and on non-standard antiretroviral therapy (ART). Patients required former viral RNA and a recent proviral DNA resistance test to be available prior to the switch to ART. Potential discrepancies between resistance test results obtained through RNA and proviral DNA methods and the consequent virological and clinical outcomes following ART adjustments were analyzed. Out of 1250 patients, 35 were eligible for inclusion in this study. The median length of known HIV infection was 27 years, and the median duration of ART was 22 years. Of the 35 participants, 16 had received all five ARV classes. Based on proviral DNA genotyping results, ART was simplified in 17 patients. At the last follow-up examination after changing therapy, 15 patients had HIV RNA <50 copies/mL (median 202 days, range 21-636). The mean number of pills per day decreased from eight to three, and the median intake frequency decreased from two to one time/day (ranges 1-2). Our study supports the use of proviral DNA genotyping as a safe strategy for switching to simplified ART regimens. However, the lack of extensive research on the advantages of proviral DNA genotyping makes it challenging to fully assess its benefits in terms of treatment selection.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Provírus/genética , Estudos Retrospectivos , Genótipo , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , DNA Viral/genética , RNA Viral/genética , Carga Viral , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética
17.
Bone Marrow Transplant ; 58(6): 639-646, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36869190

RESUMO

Cytomegalovirus (CMV) represents one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, a common diagnostic test used to stratify the risk for CMV infection in allo-HSCT recipients is the qualitative CMV serology of donor and recipient. A positive serostatus of the recipient is the most important risk factor for CMV reactivation and associated with reduced overall survival post-transplantation (TX). Direct and indirect effects of CMV are involved in the poorer survival outcome. The present study investigated if the quantitative interpretation of anti-CMV IgG before allo-HSCT might serve as a novel parameter for the identification of patients at risk for CMV reactivation and worse outcome post-TX. For this purpose, a cohort of 440 allo-HSCT recipients over a period of 10 years was retrospectively analyzed. Our findings indicated that patients with high CMV IgG pre-allo-HSCT had a higher risk to develop CMV reactivation, including clinically relevant infections, and a worse prognosis 36 months post-allo-HSCT as compared to recipients with low CMV IgG values. In the letermovir (LMV) era, this group of patients might benefit from a closer CMV monitoring, and hence, earlier intervention if needed, especially after discontinuation of prophylaxis.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Citomegalovirus/fisiologia , Anticorpos Antivirais , Imunoglobulina G
18.
Nat Med ; 29(3): 583-587, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36807684

RESUMO

Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.


Assuntos
Infecções por HIV , HIV-1 , Transplante de Células-Tronco Hematopoéticas , Masculino , Humanos , Animais , Camundongos , Pessoa de Meia-Idade , HIV-1/genética , Infecções por HIV/genética , Infecções por HIV/terapia
19.
Nat Med ; 29(11): 2763-2774, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37957379

RESUMO

Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4+ T cell counts <200 µl-1, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.


Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Humanos , Anticorpos Anti-HIV , Anticorpos Neutralizantes , Replicação Viral
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