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Persistent symptoms of COVID-19 survivors constitute long COVID syndrome, also called post-acute sequelae of SARS-CoV-2 infection (PASC). Neurologic manifestations of PASC (Neuro-PASC) are particularly debilitating, long lasting, and poorly understood. To gain insight into the pathogenesis of PASC, we leveraged a well-characterized group of Neuro-PASC (NP) patients seen at our Neuro-COVID-19 clinic who had mild acute COVID-19 and never required hospitalization to investigate their plasma proteome. Using the SomaLogic platform, SomaScan, the plasma concentration of >7000 proteins was measured from 92 unvaccinated individuals, including 48 NP patients, 20 COVID-19 convalescents (CC) without lingering symptoms, and 24 unexposed healthy controls (HC) to interrogate underlying pathobiology and potential biomarkers of PASC. We analyzed the plasma proteome based on post-COVID-19 status, neurologic and non-neurologic symptoms, as well as subjective and objective standardized tests for changes in quality-of-life (QoL) and cognition associated with Neuro-PASC. The plasma proteome of NP patients differed from CC and HC subjects more substantially than post-COVID-19 groups (NP and CC combined) differed from HC. Proteomic differences in NP patients 3-9 months following acute COVID-19 showed alterations in inflammatory proteins and pathways relative to CC and HC subjects. Proteomic associations with Neuro-PASC symptoms of brain fog and fatigue included changes in markers of DNA repair, oxidative stress, and neutrophil degranulation. Furthermore, we discovered a correlation between NP patients lower subjective impression of recovery to pre-COVID-19 baseline with an increase in the concentration of the oxidative phosphorylation protein COX7A1, which was also associated with neurologic symptoms and fatigue, as well as impairment in QoL and cognitive dysfunction. Finally, we identified other oxidative phosphorylation-associated proteins correlating with central nervous system symptoms. Our results suggest ongoing inflammatory changes and mitochondrial involvement in Neuro-PASC and pave the way for biomarker validation for use in monitoring and development of therapeutic intervention for this debilitating condition.
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COVID-19 , Proteínas Mitocondriales , Humanos , Síndrome Post Agudo de COVID-19 , Proteoma , Proteómica , Calidad de Vida , SARS-CoV-2 , Progresión de la Enfermedad , FatigaRESUMEN
Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data.
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Crotonatos/farmacología , Virus ADN/efectos de los fármacos , Hidroxibutiratos/farmacología , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Neuroglía/efectos de los fármacos , Nitrilos/farmacología , Toluidinas/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/virología , Línea Celular , Plexo Coroideo/efectos de los fármacos , Plexo Coroideo/virología , Virus ADN/patogenicidad , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/virología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/virología , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Virus JC/efectos de los fármacos , Virus JC/patogenicidad , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/patología , Leucoencefalopatía Multifocal Progresiva/virología , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/virología , Neuroglía/virología , Virosis/tratamiento farmacológico , Virosis/genética , Virosis/virologíaRESUMEN
There are only few documented cases of progressive multifocal leukoencephalopathy (PML) in Africa. Whether this is caused by a lack of JC virus (JCV) spread or alteration in the JCV genome is unknown. We characterized the clinical presentation, laboratory findings, and JCV regulatory region (RR) pattern of the first documented PML cases in Zambia as well as JCV seroprevalence among HIV+ and HIV- Zambians. We identified PML patients with positive JCV DNA PCR in their cerebrospinal fluid (CSF) among subjects enrolled in an ongoing tuberculous meningitis study from 2014 to 2016 in Lusaka. JCV regulatory region was further characterized by duplex PCR in patients' urine and CSF. Of 440 HIV+ patients, 14 (3%) had detectable JCV DNA in their CSF (age 18-50; CD4+ T cells counts 15-155 × 106/µl) vs 0/60 HIV- patients. The main clinical manifestations included altered mental status and impaired consciousness consistent with advanced PML. While prototype JCV was identified by duplex PCR assay in the CSF samples of all 14 PML patients, only archetype JCV was detected in their urine. All PML Zambian patients tested were seropositive for JCV compared to 46% in a control group of HIV+ and HIV- Zambian patients without PML. PML occurs among HIV-infected individuals in Zambia and is caused by CNS infection with prototype JCV, while archetype JCV strains are present in their urine. JCV seroprevalence is comparable in Zambia and the USA, and PML should be included in the differential diagnosis of immunosuppressed individuals presenting with neurological dysfunction in Zambia.
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ADN Viral/genética , Infecciones por Henipavirus/diagnóstico , Virus JC/genética , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Tuberculosis Meníngea/diagnóstico , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , Coinfección , ADN Viral/líquido cefalorraquídeo , ADN Viral/orina , Femenino , Genotipo , VIH/efectos de los fármacos , VIH/genética , VIH/aislamiento & purificación , Infecciones por Henipavirus/líquido cefalorraquídeo , Infecciones por Henipavirus/tratamiento farmacológico , Infecciones por Henipavirus/virología , Humanos , Virus JC/efectos de los fármacos , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/líquido cefalorraquídeo , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Leucoencefalopatía Multifocal Progresiva/virología , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/virología , ZambiaRESUMEN
Background: Cytomegalovirus (CMV) has been linked to higher risk of cardiovascular disease and mortality. We aimed to determine if CMV is associated with neurocognitive performance in adults infected with human immunodeficiency virus (HIV). Methods: In this cross-sectional analysis, anti-CMV immunoglobulin G (IgG) concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV-infected adults who were previously assessed with a comprehensive neurocognitive test battery. Thirty-eight were taking suppressive antiretroviral therapy (ART) and 42 were not taking ART. A panel of 7 soluble biomarkers was measured by immunoassay in CSF. Results: Anti-CMV IgG concentrations ranged from 5.2 to 46.1 IU/mL. CMV DNA was detected in 7 (8.8%) plasma specimens but in no CSF specimens. Higher anti-CMV IgG levels were associated with older age (P = .0017), lower nadir CD4+ T-cell count (P < .001), AIDS (P < .001), and higher soluble CD163 (P = .009). Higher anti-CMV IgG levels trended toward an association with worse neurocognitive performance overall (P = .059). This correlation was only present in those taking suppressive ART (P = .0049). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (model P = .0038). Detectable plasma CMV DNA was associated with AIDS (P = .05) but not with neurocognitive performance. Conclusions: CMV may influence neurocognitive performance in HIV-infected adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help to determine whether the observed relationships are causal.
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Anticuerpos Antivirales/sangre , Infecciones por Citomegalovirus/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inmunoglobulina G/sangre , Trastornos Neurocognitivos/etiología , Adulto , Factores de Edad , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Estudios Transversales , Citomegalovirus , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/inmunología , ADN Viral/sangre , ADN Viral/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Trastornos Neurocognitivos/virología , Carga ViralRESUMEN
Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-ß (CD8+). Immunocytochemical analysis showed induction of amyloid-ß in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-ß. These data support an association between CMV and the development of Alzheimer disease.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/análisis , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Infecciones por Citomegalovirus/complicaciones , Femenino , Fibroblastos/química , Fibroblastos/virología , Humanos , Interferón gamma/líquido cefalorraquídeo , Masculino , Ovillos Neurofibrilares/metabolismo , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Viruses can infect the brain in individuals with and without HIV-infection: however, the brain virome is poorly characterized. Metabolic alterations have been identified which predispose people to substance use disorder (SUD), but whether these could be triggered by viral infection of the brain is unknown. We used a target-enrichment, deep sequencing platform and bioinformatic pipeline named "ViroFind", for the unbiased characterization of DNA and RNA viruses in brain samples obtained from the National Neuro-AIDS Tissue Consortium. We analyzed fresh frozen post-mortem prefrontal cortex from 72 individuals without known viral infection of the brain, including 16 HIV+/SUD+, 20 HIV+/SUD-, 16 HIV-/SUD+, and 20 HIV-/SUD-. The average age was 52.3 y and 62.5% were males. We identified sequences from 26 viruses belonging to 11 viral taxa. These included viruses with and without known pathogenic potential or tropism to the nervous system, with sequence coverage ranging from 0.03 to 99.73% of the viral genomes. In SUD+ people, HIV-infection was associated with a higher total number of viruses, and HIV+/SUD+ compared to HIV-/SUD+ individuals had an increased frequency of Adenovirus (68.8 vs 0%; p<0.001) and Epstein-Barr virus (EBV) (43.8 vs 6.3%; p=0.037) as well as an increase in Torque Teno virus (TTV) burden. Conversely, in HIV+ people, SUD was associated with an increase in frequency of Hepatitis C virus, (25 in HIV+/SUD+ vs 0% in HIV+/SUD-; p=0.031). Finally, HIV+/SUD- compared to HIV-/SUD- individuals had an increased frequency of EBV (50 vs 0%; p<0.001) and an increase in TTV viral burden, but a decreased Adenovirus viral burden. These data demonstrate an unexpectedly high variety in the human brain virome, identifying targets for future research into the impact of these taxa on the central nervous system. ViroFind could become a valuable tool for monitoring viral dynamics in various compartments, monitoring outbreaks, and informing vaccine development.
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Infecciones por Virus ADN , Infecciones por Virus de Epstein-Barr , Infecciones por VIH , Trastornos Relacionados con Sustancias , Torque teno virus , Virosis , Masculino , Humanos , Persona de Mediana Edad , Femenino , Viroma , Infecciones por Virus de Epstein-Barr/complicaciones , ADN Viral/genética , Herpesvirus Humano 4/genética , Infecciones por VIH/epidemiología , Virosis/complicaciones , Torque teno virus/genética , Encéfalo , Hepacivirus/genética , Trastornos Relacionados con Sustancias/complicacionesRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1155770.].
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Introduction: Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. Results: We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. Discussion: We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.
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Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , COVID-19 , Síndrome Post Agudo de COVID-19 , Humanos , COVID-19/inmunología , Interleucina-6 , Síndrome Post Agudo de COVID-19/inmunología , SARS-CoV-2RESUMEN
Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells. Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.
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BACKGROUND AND OBJECTIVES: Although patients hospitalized with COVID-19 frequently present with encephalopathy, those with mild initial COVID-19 disease who never required hospitalization also often develop neurologic symptoms as part of postacute sequelae of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection (neuro-PASC). The pathogenic mechanisms of COVID-19 encephalopathy and neuro-PASC are unknown. We sought to establish biochemical evidence of CNS injury in those patients and their association with neuropsychiatric manifestations and SARS-CoV-2 antigenemia. METHODS: We recruited hospitalized, posthospitalized, and nonhospitalized patients with confirmed diagnosis of COVID-19 with neurologic symptoms in addition to healthy control (HC) subjects. Plasma neurofilament light chain (pNfL), plasma glial fibrillary acidic protein (pGFAP), and plasma SARS-CoV-2 Nucleocapsid antigen (pN Ag) were measured by HD-X Simoa analyzer (Quanterix) and compared with neuropsychiatric symptoms, patient-reported quality-of-life measures, and standardized cognitive assessments. Neuroglial scores (pGFAP/pNfL) were calculated to estimate the relative contribution of astroglial and neuronal involvement. RESULTS: We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures. DISCUSSION: pNfL, pGFAP, and pN Ag measurements indicate neuronal dysfunction and systemic involvement in hospitalized COVID-19 patients with encephalopathy. Detection of SARS-CoV-2 N Ag in blood 3 weeks after symptoms onset in a nonhospitalized patient suggests that prolonged antigenic stimulation, or possibly latent infection, may occur. Anxiety was associated with evidence of astroglial activation in patients with neuro-PASC. These data shed new light on SARS-Cov-2 neuropathogenesis and demonstrate the value of plasma biomarkers across the COVID-19 disease spectrum.
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COVID-19 , Disfunción Cognitiva , Biomarcadores , COVID-19/complicaciones , Progresión de la Enfermedad , Humanos , SARS-CoV-2RESUMEN
Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.g., leukemias, lymphomas, and multiple myeloma), autoimmune disorders (e.g., psoriasis, rheumatoid arthritis, and systemic lupus erythematosus), and organ transplants. In some patients, iatrogenic (i.e., drug-induced) PML occurs as a serious adverse event from exposure to immunosuppressant therapies used to treat their disease (e.g., hematological malignancies and multiple sclerosis). While JCV infection and immunosuppression are necessary, they are not sufficient to cause PML. Methods: We hypothesized that patients may also have a genetic susceptibility from the presence of rare deleterious genetic variants in immune-relevant genes (e.g., those that cause inborn errors of immunity). In our prior genetic study of 184 PML cases, we discovered 19 candidate PML risk variants. In the current study of another 152 cases, we validated 4 of 19 variants in both population controls (gnomAD 3.1) and matched controls (JCV+ multiple sclerosis patients on a PML-linked drug ≥ 2 years). Results: The four variants, found in immune system genes with strong biological links, are: C8B, 1-57409459-C-A, rs139498867; LY9 (alias SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; STXBP2, 19-7712287-G-C, rs35490401. Carriers of any one of these variants are shown to be at high risk of PML when drug-exposed PML cases are compared to drug-exposed matched controls: P value = 3.50E-06, OR = 8.7 [3.7-20.6]. Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Conclusion: For the first time, a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug in order to decrease the incidence of PML and enable safer use of highly effective therapies used to treat their underlying disease.
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Cybernetic causality reveals social processes of blaming. It allows for fluid multidirectional causal webs. Looking at blame through a cybernetic lens reveals social construction processes of creation, modification, exacerbation, dissipation, and elimination. Sometimes all at the same time. Performances of blaming can attribute praise or condemnation both simultaneously and sequentially. Blaming is enacted in multiple forms including being a conduit, reducing uncertainty, separation from self, a desire for efficacy, or a search for esteem. Mapping out fluid complexity in blaming might encourage using cybernetic causality to understand more aspects of social experience.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-ß (Aß) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).
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Antivirales/farmacología , Infecciones por Virus ADN/metabolismo , Virus ADN/efectos de los fármacos , Infecciones por Virus ARN/metabolismo , Virus ARN/efectos de los fármacos , Salicilatos/farmacología , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Astrocitos/metabolismo , Chlorocebus aethiops , Replicación del ADN/efectos de los fármacos , Infecciones por Virus ADN/virología , Virus ADN/genética , ADN Viral/genética , Células HEK293 , Humanos , Infecciones por Virus ARN/virología , Virus ARN/genética , Células Vero , Proteínas del Envoltorio Viral/biosíntesis , Proteínas Virales de Fusión/biosíntesis , Virión/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases. A PML risk prediction test would have clinical utility in all at risk patient groups but would be particularly beneficial in patients considering therapy with immunosuppressant agents known to cause PML, such as natalizumab, rituximab, and others. While a JC antibody test is currently used in the clinical decision process for natalizumab, it is suboptimal because of its low specificity and requirement to periodically retest patients for seroconversion or to assess if a patient's JCV index has increased. Whereas a high specificity genetic risk prediction test comprising host genetic risk variants (i.e., germline variants occurring at higher frequency in PML patients compared to the general population) could be administered one time to provide clinicians with additional risk prediction information that is independent of JCV serostatus. Prior PML case reports support the hypothesis that PML risk is greater in patients with a genetically caused immunodeficiency disorder. To identify germline PML risk variants, we performed exome sequencing on 185 PML cases (70 in a discovery cohort and 115 in a replication cohort) and used the gnomAD variant database for interpretation. Our study yielded 19 rare variants (maximum allele frequency of 0.02 in gnomAD ethnically matched populations) that impact 17 immune function genes (10 are known to cause inborn errors of immunity). Modeling of these variants in a PML genetic risk test for MS patients considering natalizumab treatment indicates that at least a quarter of PML cases may be preventable.
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Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups (p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIV-infected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association (p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.
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Coinfección/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Antivirales/sangre , Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Biomarcadores/sangre , Coinfección/sangre , Coinfección/virología , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inmunoglobulina G/sangre , Inflamación/inmunología , Inflamación/virología , Interferón gamma/sangre , Interleucina-6/sangre , Receptores de Lipopolisacáridos/sangre , Persona de Mediana Edad , Raltegravir Potásico/uso terapéutico , Receptores de Superficie Celular/sangre , Carga Viral , Viremia/virologíaAsunto(s)
Anticuerpos Antivirales/sangre , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Infecciones por Citomegalovirus/complicaciones , Citomegalovirus/inmunología , Infecciones por VIH/sangre , Receptores de Lipopolisacáridos/metabolismo , Receptores de Superficie Celular/metabolismo , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/inmunología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana EdadRESUMEN
The belief that fertility problems derive from maternal age, increasing markedly at 35, reflects social constructions of biology in developed nations. These constructions perpetuate a negative view of female aging. However, research since 1985 can be interpreted to suggest that there is no, or minimal, association between maternal age and problems associated with fertility. Differences in problems between pre- and postmaternal age 35 fertility can be explained by social conditions occurring with fertility, notably, parenting decisions, physical problems with the male and the potential child, and medical intervention. Once we look at fertility as a relationship among the woman, the man, and the potential child, rather than the woman only, we can see these factors. These components suggest that maternal age may be related only tangentially to successful fertility.