RESUMEN
PURPOSE: The aim of the study was to determine outcomes after heart transplantation for cytomegalovirus (CMV) mismatched patients (D+/R-) who underwent a surveillance and preemptive therapy protocol, compared to nonmismatch patients. METHODS: A review of patient records from January 2010 to December 2020 with follow-up to October 2023 was done. The protocol consisted weekly surveillance with CMV PCR starting 4 weeks after transplant continuing up until the patient seroconverts or up to 3 months posttransplant if the patient does not seroconvert. Valganciclovir was given for 2 weeks to those who seroconverted. RESULTS: Two hundred and twenty-one patients were included, and 23% were mismatched patients. Overall survival was not different between CMV groups (p = NS). Causes of death and morbidities were also not significantly different (p = NS). Sixty-six percent of mismatch patients seroconverted, and there was also a significantly older donor age in the seroconverted patients compared to nonseroconverted patients (41 ± 11 vs. 29 ± 12 years, p < 0.005), indicating a higher risk donor profile. A multivariate Cox regression including donor age showed that there was no increase in mortality in the seroconverted mismatches compared to nonmismatch patients (p = NS). CONCLUSIONS: There is no significant increased mortality or morbidity using a CMV surveillance and preemptive therapy protocol. The effect of donor age on seroconversion of mismatches requires further validation.
Asunto(s)
Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Supervivencia de Injerto , Trasplante de Corazón , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/epidemiología , Femenino , Masculino , Citomegalovirus/aislamiento & purificación , Estudios de Seguimiento , Adulto , Pronóstico , Estudios Retrospectivos , Antivirales/uso terapéutico , Factores de Riesgo , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Tasa de Supervivencia , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Donantes de Tejidos/provisión & distribuciónRESUMEN
Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.
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Animales Recién Nacidos , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Citomegalovirus , Ratones Noqueados , Animales , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/virología , Proteínas Priónicas/metabolismo , Proteínas Priónicas/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proteína ADAM10/metabolismo , Proteína ADAM10/genéticaRESUMEN
Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV's 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.
Asunto(s)
Carcinoma Epitelial de Ovario , Trompas Uterinas , Papillomavirus Humano 16 , Neoplasias Ováricas , Infecciones por Papillomavirus , Humanos , Femenino , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Factores de Riesgo , Carcinoma Epitelial de Ovario/virología , Carcinoma Epitelial de Ovario/patología , Persona de Mediana Edad , Trompas Uterinas/virología , Trompas Uterinas/patología , Adulto , Anciano , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Neoplasias Ováricas/virología , Neoplasias Ováricas/patología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Citomegalovirus/aislamiento & purificación , Citomegalovirus/genética , ADN Viral/genéticaRESUMEN
Genetic parasites, including viruses and transposons, exploit components from the host for their own replication. However, little is known about virus-transposon interactions within host cells. Here, we discover a strategy where human cytomegalovirus (HCMV) hijacks L1 retrotransposon encoded protein during its replication cycle. HCMV infection upregulates L1 expression by enhancing both the expression of L1-activating transcription factors, YY1 and RUNX3, and the chromatin accessibility of L1 promoter regions. Increased L1 expression, in turn, promotes HCMV replicative fitness. Affinity proteomics reveals UL44, HCMV DNA polymerase subunit, as the most abundant viral binding protein of the L1 ribonucleoprotein (RNP) complex. UL44 directly interacts with L1 ORF2p, inducing DNA damage responses in replicating HCMV compartments. While increased L1-induced mutagenesis is not observed in HCMV for genetic adaptation, the interplay between UL44 and ORF2p accelerates viral DNA replication by alleviating replication stress. Our findings shed light on how HCMV exploits host retrotransposons for enhanced viral fitness.
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Citomegalovirus , Replicación del ADN , Elementos de Nucleótido Esparcido Largo , Proteínas Virales , Replicación Viral , Humanos , Citomegalovirus/genética , Citomegalovirus/fisiología , Replicación Viral/genética , Proteínas Virales/metabolismo , Proteínas Virales/genética , Replicación del ADN/genética , Elementos de Nucleótido Esparcido Largo/genética , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/genética , Interacciones Huésped-Patógeno/genética , Retroelementos/genética , Proteínas de Unión al ADNRESUMEN
Human cytomegalovirus (HCMV) glycoprotein B (gB) is a class III membrane fusion protein required for viral entry. HCMV vaccine candidates containing gB have demonstrated moderate clinical efficacy, but no HCMV vaccine has been approved. Here, we used structure-based design to identify and characterize amino acid substitutions that stabilize gB in its metastable prefusion conformation. One variant containing two engineered interprotomer disulfide bonds and two cavity-filling substitutions (gB-C7), displayed increased expression and thermostability. A 2.8 Å resolution cryoelectron microscopy structure shows that gB-C7 adopts a prefusion-like conformation, revealing additional structural elements at the membrane-distal apex. Unlike previous observations for several class I viral fusion proteins, mice immunized with postfusion or prefusion-stabilized forms of soluble gB protein displayed similar neutralizing antibody titers, here specifically against an HCMV laboratory strain on fibroblasts. Collectively, these results identify initial strategies to stabilize class III viral fusion proteins and provide tools to probe gB-directed antibody responses.
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Citomegalovirus , Proteínas del Envoltorio Viral , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/metabolismo , Citomegalovirus/inmunología , Humanos , Animales , Ratones , Microscopía por Crioelectrón , Conformación Proteica , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Internalización del Virus , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Estabilidad Proteica , Vacunas contra Citomegalovirus/inmunología , Sustitución de Aminoácidos , Modelos MolecularesRESUMEN
OBJECTIVE: Congenital cytomegalovirus infection (cCMV) is a common, frequently unrecognized cause of childhood disability. The aim of the present study was to determine the symptoms that raise the suspicion of cCMV, define the neurodevelopmental outcomes, and assess their correlations. METHODS: This longitudinal observational study comprised 78 children with symptomatic cCMV who underwent neuropediatric follow-up for 4 to 17.9 years. RESULTS: Symptoms of central nervous system involvement, hearing/visual impairments, and hepatic involvement were mostly recognized. The average age of disease suspicion was 3.3 months. In terms of outcomes, 10.53% of the children developed complex minor neurological dysfunction and 23.68% developed cerebral palsy. Visual and hearing impairments occurred in 38.16% and 14.47% of patients, respectively. Intellectual disability was present in 30.26% of patients, and epilepsy in 21.05%. Microcephaly and hearing impairment was significantly associated with overall neurodevelopmental outcome. Microcephaly was also associated with poor motor outcomes, hearing impairment, and severe visual impairment. Furthermore, microcephaly and intrauterine growth restriction were significantly associated with poor cognitive outcomes. CONCLUSION: Symptoms that raised the suspicion of cCMV-especially microcephaly, hearing impairment, and intrauterine growth restriction-were important parameters that were associated with outcomes; however, their recognition was often insufficient and/or late.
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Infecciones por Citomegalovirus , Humanos , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/diagnóstico , Femenino , Masculino , Niño , Preescolar , Lactante , Adolescente , Estudios Longitudinales , Microcefalia/virología , Microcefalia/etiología , Parálisis Cerebral , Pérdida Auditiva/virología , Pérdida Auditiva/etiología , Pérdida Auditiva/diagnóstico , Discapacidad Intelectual/virología , Retardo del Crecimiento Fetal/virología , Trastornos de la Visión/virología , Trastornos de la Visión/etiología , Trastornos de la Visión/diagnóstico , Recién Nacido , Pronóstico , Citomegalovirus/patogenicidad , Estudios de SeguimientoRESUMEN
Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.
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Acetatos , Antivirales , Infecciones por Citomegalovirus , Trasplante de Órganos , Quinazolinas , Ribonucleósidos , Humanos , Infecciones por Citomegalovirus/tratamiento farmacológico , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacología , Ribonucleósidos/uso terapéutico , Ribonucleósidos/efectos adversos , Ribonucleósidos/farmacología , Trasplante de Órganos/efectos adversos , Acetatos/uso terapéutico , Acetatos/efectos adversos , Acetatos/farmacología , Quinazolinas/uso terapéutico , Quinazolinas/farmacología , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Citomegalovirus/efectos de los fármacos , Diclororribofuranosil Benzoimidazol/análogos & derivadosRESUMEN
OBJECTIVE: To document the course of neonatal and short-term outcomes in pregnancies after first trimester CMV (cytomegalovirus) seroconversion and negative amniotic fluid (AF) CMV PCR. METHODS: We included 375 patients with a first-trimester CMV seroconversion and amniocentesis at ≥21 weeks. Termination of pregnancy (TOP) was offered in case antenatally severe CMV-related fetopathy was documented either by ultrasound or by MRI. AF CMV PCR-negative fetuses underwent a PCR CMV on neonatal urine (NU). Perinatal and short-term infant outcomes were investigated by a questionnaire, sent to parents. RESULTS: AF CMV PCR was positive in 118/375 cases (31.4%). TOP was performed in 46/118 (38.9%) and fetal demise occurred twice. Questionnaires were sent to 327 patients with an overall response rate of 77%. Three groups were considered: Group 1: the early infected group (AF CMV PCR positive; N=62), group 2: the late infected group (AF CMV PCR negative, NU CMV PCR positive; N=7) and group 3: the control group (AF+NU CMV PCR negative; N=160). Compared with group 3, group 1 was more frequently symptomatic at birth (6.2% vs 19.4%; p=0.006). In short-term follow-up, hearing impairment (23.5%; p<0.001), mild motor deficit - defined as abnormal early motor development or the need for physiotherapy in later life (21.6%; p=0.005) - and subnormal vision (15.7%; p=0.02) were significantly more frequent. Compared with group 3, group 2 showed more often jaundice (57.1%; p=0.04) and petechiae (28.6%; p=0.04) at birth, but other short-term symptoms were lacking. CONCLUSION: Although neonates may screen positive on urine for CMV after an AF CMV negative PCR, they show rarely and only mild sequelae in early life.
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Infecciones por Citomegalovirus , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Primer Trimestre del Embarazo , Seroconversión , Humanos , Embarazo , Femenino , Infecciones por Citomegalovirus/transmisión , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/congénito , Recién Nacido , Complicaciones Infecciosas del Embarazo/virología , Adulto , Citomegalovirus/inmunología , Citomegalovirus/aislamiento & purificación , Amniocentesis , Líquido Amniótico/virología , Reacción en Cadena de la Polimerasa , Resultado del Embarazo/epidemiología , MasculinoRESUMEN
AIMS: This study aims to evaluate the presence of EBV, HCMV, and BKV genomic sequences in the plasma samples (active infection/viremia) of kidney transplant recipients suspected of rejection and to investigate host and risk factors related to the activation of these viruses in these patients. METHODS: In this cross-sectional single-center study, plasma samples were collected from 98 suspected kidney transplant rejection patients at Labafinejad Hospital, Tehran, Iran, between December 2022 and June 2023. Quantitative real-time PCR assays for HCMV, EBV, and BK were performed using GeneProof Real-time PCR kits. ROC curve analysis was used to determine the viral load cutoff point for each virus. FINDINGS: HCMV active viremia was detected in 18 (18.36%) recipients, EBV active viremia in 7 (7.14%), and BKV active viremia in 5 (5.10%). ROC results indicated viral load cutoff points of 778, 661, and 457 points for HCMV, EBV, and BKV, respectively. The duration of time after transplantation significantly differed between active viremia and no viremia groups (120.5 vs. 46 months, P = 0.014). In the BKV active viremia group, the increase in creatinine compared to baseline creatinine was significantly higher than in the no viremia group (2.7 vs. 0.8, P = 0.017). The odds ratio of HCMV active viremia in patients taking tacrolimus was 2.84 times higher, and the odds of HCMV active viremia in patients taking antithymocyte globulin was 3.01 times higher than in patients not taking these drugs. CONCLUSION: Rapid and timely diagnosis of viral active infections in kidney transplant patients is crucial for effective disease management and implementation of appropriate treatment strategies. Identifying potential risk factors, including host and treatment-related factors that influence transplantation, can facilitate the development of suitable preventive strategies.
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Virus BK , Infecciones por Citomegalovirus , Citomegalovirus , Infecciones por Virus de Epstein-Barr , Rechazo de Injerto , Herpesvirus Humano 4 , Trasplante de Riñón , Infecciones por Polyomavirus , Carga Viral , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Virus BK/aislamiento & purificación , Virus BK/genética , Adulto , Estudios Transversales , Infecciones por Polyomavirus/virología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Citomegalovirus/virología , Citomegalovirus/aislamiento & purificación , Citomegalovirus/genética , Rechazo de Injerto/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Irán/epidemiología , Factores de Riesgo , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/sangre , Anciano , Adulto Joven , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
PURPOSE: Evaluate cytomegalovirus (CMV) post-prophylaxis surveillance in high-risk (D+/R-) kidney and liver transplant recipients. METHODS: Adult D+/R- patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre-CMV-stewardship-era (6/1/15-5/31/18), CMV-stewardship-era (6/1/18-6/30/20), and a surveillance-era (7/1/2020-11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV-related outcomes. The secondary objective was to assess graft and patient survival by era. RESULTS: There were 328 patients in the study period; 133 in the pre-stewardship-era, 103 in the stewardship-era, and 92 in the surveillance-era. Replication rates in the surveillance-era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum-VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end-organ disease (p < 0.0001) and ganciclovir-resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era. CONCLUSIONS: Post-prophylaxis surveillance significantly reduced CMV end-organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months.
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Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Farmacorresistencia Viral , Ganciclovir , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Riñón , Trasplante de Hígado , Humanos , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Citomegalovirus/aislamiento & purificación , Citomegalovirus/efectos de los fármacos , Antivirales/uso terapéutico , Ganciclovir/uso terapéutico , Estudios de Seguimiento , Trasplante de Hígado/efectos adversos , Factores de Riesgo , Trasplante de Riñón/efectos adversos , Pronóstico , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Rechazo de Injerto/virología , Complicaciones Posoperatorias/prevención & control , Adulto , Tasa de Supervivencia , Estudios Retrospectivos , Receptores de Trasplantes/estadística & datos numéricosAsunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Feto , Humanos , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/patología , Femenino , Embarazo , Citomegalovirus/genética , Feto/virología , Feto/patología , Feto/diagnóstico por imagen , Líquido Amniótico/virología , Imagen por Resonancia Magnética , Estudios Retrospectivos , Ultrasonografía Prenatal , Retardo del Crecimiento Fetal/virología , Enfermedades Fetales/virología , Enfermedades Fetales/patología , Complicaciones Infecciosas del Embarazo/virología , Complicaciones Infecciosas del Embarazo/patología , AutopsiaRESUMEN
BACKGROUND/AIM: Wilms' tumors are pediatric renal tumors that generally have a good prognosis and outcomes. Viral illnesses have been linked to development of neoplasms and should be considered as a factor that could modulate overall survival. MATERIALS AND METHODS: We considered recently developed adaptive immune receptor, genomics and bioinformatics approaches to assess the potential impact of cytomegalovirus (CMV) infections in Wilms' tumor. RESULTS: T-cell receptor (TCR) complementarity determining region-3 (CDR3) amino acid sequences from Wilms' tumor specimens represented by the Therapeutically Applicable Research to Generate Effective Treatments dataset were compared with known anti-CMV TCR CDR3s, indicating that cases representing the anti-CMV TCR CDR3s had worse outcomes. Then, a chemical complementarity scoring approach for the Wilms' tumor, TCR CDR3s and a series of CMV antigens further indicated that cases representing a higher chemical complementarity to the CMV antigens had worse outcomes. CONCLUSION: Overall, we present a potentially novel method to assess CMV infections and identify patients who could benefit from therapies that address such infections.
Asunto(s)
Regiones Determinantes de Complementariedad , Citomegalovirus , Neoplasias Renales , Receptores de Antígenos de Linfocitos T , Tumor de Wilms , Humanos , Tumor de Wilms/inmunología , Tumor de Wilms/genética , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Renales/inmunología , Neoplasias Renales/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Pronóstico , Epítopos/inmunologíaRESUMEN
PURPOSE OF REVIEW: Although there are multiple benefits of mother's own milk feeding for very-low birth weight, low gestation infants, those born to cytomegalovirus (CMV)-seropositive mothers are at risk for acquiring postnatal CMV infection. This review will describe the risk and consequences of postnatal CMV infection among very preterm infants. RECENT FINDINGS: Postnatal CMV may manifest as clinically silent infection or as mild to severe and occasionally fatal disease. The risk of disease is balanced by the health benefits of human milk feeding to preterm infants. Postnatal CMV infection has been associated with increased risks of multiple preterm morbidities such as bronchopulmonary dysplasia, necrotizing enterocolitis and neurodevelopmental impairment, but current evidence is limited by the selection bias inherent to reporting in case series and retrospective cohort studies. SUMMARY: Knowledge gaps exist regarding the risk-benefit balance of pasteurization to inactivate CMV in fresh breast milk, as well as the optimal dosing, duration and efficacy of treating infected infants with antiviral medications. Multicenter, prospective studies are urgently needed to accurately determine the true burden that postnatal CMV infection presents to very preterm infants. Such studies will inform the need for preventive strategies and treatment guidance.
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Infecciones por Citomegalovirus , Recien Nacido Prematuro , Leche Humana , Humanos , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/transmisión , Recién Nacido , Leche Humana/virología , Citomegalovirus , Antivirales/uso terapéutico , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Femenino , Lactancia MaternaRESUMEN
Cytomegalovirus infection contributes to 10-30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections and reactivation and affect healthy adults to a lesser extent. This may be due to the fact that viral infections affect signaling pathways that are important for the development of peripheral hearing organs. Therefore, an in-depth understanding of the relationship between viral infections and the signaling pathways involved in the development of peripheral hearing organs is important for the prevention and treatment of ear diseases. In this review, we summarize the effects of viruses on signaling pathways and signaling molecules in the development of peripheral auditory organs.
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Transducción de Señal , Virosis , Humanos , Animales , Virosis/metabolismo , Virosis/virología , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/metabolismo , Citomegalovirus/fisiología , Citomegalovirus/genéticaRESUMEN
Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein-coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.
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Citomegalovirus , Receptores ErbB , Monocitos , Proteínas Proto-Oncogénicas c-akt , Proteínas Virales , Replicación Viral , Citomegalovirus/fisiología , Citomegalovirus/genética , Citomegalovirus/metabolismo , Humanos , Monocitos/virología , Monocitos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosforilación , Proteínas Virales/metabolismo , Proteínas Virales/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Virión/metabolismo , Virión/genética , Receptores de Quimiocina/metabolismo , Receptores de Quimiocina/genética , Infecciones por Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/genética , Transducción de SeñalRESUMEN
Human cytomegalovirus (HCMV) infection remains a major complication for solid organ transplant recipients (SOTRs). The aim of this study was to evaluate the role of HCMV-specific T cell immunity measured at the time of the HCMV-DNA peak in predicting the spontaneous clearance of infection. The performance of cytokine flow cytometry using infected dendritic cells (CFC-iDC), infected cell lysate (CFC-iCL) and pp65 peptide pool (CFC-pp65 pool) as stimuli, as well as ELISPOT assays using infected cell lysate (ELISPOT-iCL) and the pp65 peptide pool (ELISPOT-pp65 pool), was analysed. Among the 40 SOTRs enrolled, 16 patients (40%) required antiviral treatment for an HCMV infection (Non-Controllers), while the others spontaneously cleared the infection (Controllers). At the HCMV-DNA peak, the number of HCMV-specific CD4+ T cells detected by the CFC-iDC, CFC-iCL and CFC-pp65 pool assays in Controllers was higher than that detected in Non-Controllers, while no difference was observed in terms of HCMV-specific CD8+ T cell response. The same trend was observed when the HCMV-specific T cell response was measured by ELISPOT-iCL and ELISPOT-pp65 pool. We observed that the CD4+ CFC-pp65 pool assay was the best predictor of self-resolving HCMV infection at the time of the HCVM-DNA peak. The CFC-pp65 pool assay is able to discriminate between CD4+ and CD8+ T cell responses and could be used in daily clinical practice.
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Infecciones por Citomegalovirus , Citomegalovirus , Receptores de Trasplantes , Humanos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Trasplante de Órganos/efectos adversos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Anciano , ADN Viral , Células Dendríticas/inmunología , Ensayo de Immunospot Ligado a Enzimas , Pruebas Inmunológicas/métodos , Citocinas/metabolismoRESUMEN
Herpesviral protein kinases, such as the therapy-relevant pUL97 of human cytomegalovirus (HCMV), are important for viral replication efficiency as well as pathogenesis, and represent key antiviral drug targets. HCMV pUL97 is a viral cyclin-dependent kinase (CDK) ortholog, as it shares functional and structural properties with human CDKs. Recently, the formation of vCDK/pUL97-cyclin complexes and the phosphorylation of a variety of viral and cellular substrate proteins has been demonstrated. Genetic mapping and structural modeling approaches helped to define two pUL97 interfaces, IF1 and IF2, responsible for cyclin binding. In particular, the regulatory importance of interactions between vCDK/pUL97 and host cyclins as well as CDKs has been highlighted, both as determinants of virus replication and as a novel drug-targeting option. This aspect was substantiated by the finding that virus replication was impaired upon cyclin type H knock-down, and that such host-directed interference also affected viruses resistant to existing therapies. Beyond the formation of binary interactive complexes, a ternary pUL97-cyclin H-CDK7 complex has also been described, and in light of this, an experimental trans-stimulation of CDK7 activity by pUL97 appeared crucial for virus-host coregulation. In accordance with this understanding, several novel antiviral targeting options have emerged. These include kinase inhibitors directed to pUL97, to host CDKs, and to the pUL97-cyclin H interactive complexes. Importantly, a statistically significant drug synergy has recently been reported for antiviral treatment schemes using combinations of pharmacologically relevant CDK7 and vCDK/pUL97 inhibitors, including maribavir. Combined, such findings provide increased options for anti-HCMV control. This review focuses on regulatory interactions of vCDK/pUL97 with the host cyclin-CDK apparatus, and it addresses the functional relevance of these key effector complexes for viral replication and pathogenesis. On this basis, novel strategies of antiviral drug targeting are defined.
Asunto(s)
Antivirales , Quinasas Ciclina-Dependientes , Citomegalovirus , Proteínas Virales , Humanos , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/fisiología , Proteínas Virales/metabolismo , Proteínas Virales/química , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Animales , Ciclinas/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)RESUMEN
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.
Asunto(s)
Presentación de Antígeno , Linfocitos T CD8-positivos , Reactividad Cruzada , Infecciones por Citomegalovirus , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Reactividad Cruzada/inmunología , Presentación de Antígeno/inmunología , Infecciones por Citomegalovirus/inmunología , Muromegalovirus/inmunología , Apoptosis , Citomegalovirus/inmunología , Células Presentadoras de Antígenos/inmunología , Ratones Endogámicos C57BL , Antígenos Virales/inmunologíaRESUMEN
Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV.