Rearrangement of the JC virus regulatory region sequence in the bone marrow of a patient with rheumatoid arthritis and progressive multifocal leukoencephalopathy

Q3Q2Reporte de caso455-458The polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML). JCV remains quiescent in kidneys, where it displays a stable archetypal regulatory region (RR). Conversely, rearranged JCV RR, including tandem repeat patterns found in the central nervous system (CNS) of PML patients, have been associated with neurovirulence. The precise site and mechanism of JCV RR transformation is unknown. We present herein a patient with rheumatoid arthritis treated with methotrexate, who developed PML and had a rapid fatal outcome. JCV DNA polymerase chain reaction (PCR) was positive in cerebrospinal fluid (CSF), bone marrow, blood, and urine. Double-immunohistochemical staining demonstrated that 9% of bone marrow CD138+ plasma cells sustained productive infection by JCV, accounting for 94% of JCV-infected cells. JCV RR analysis revealed archetype and rearranged RR forms in bone marrow, whereas RR with tandem repeat was predominant in blood. These results suggest that the bone marrow may be a potential site of JCV pathogenic transformation. Further studies will be needed to determine the prevalence of JCV in bone marrow of immunosuppressed individuals at risk of PML and characterize the RR and phenotype of these JCV isolates

Comparative determination of HIV-1 co-receptor tropism by Enhanced Sensitivity Trofile, gp120 V3-loop RNA and DNA genotyping

BACKGROUND: Trofile is the prospectively validated HIV-1 tropism assay. Its use is limited by high costs, long turn-around time, and inability to test patients with very low or undetectable viremia. We aimed at assessing the efficiency of population genotypic assays based on gp120 V3-loop sequencing for the determination of tropism in plasma viral RNA and in whole-blood viral DNA. Contemporary and follow-up plasma and whole-blood samples from patients undergoing tropism testing via the enhanced sensitivity Trofile (ESTA) were collected. Clinical and clonal geno2pheno[coreceptor] (G2P) models at 10% and at optimised 5.7% false positive rate cutoff were evaluated using viral DNA and RNA samples, compared against each other and ESTA, using Cohen's kappa, phylogenetic analysis, and area under the receiver operating characteristic (AUROC). RESULTS: Both clinical and clonal G2P (with different false positive rates) showed good performances in predicting the ESTA outcome (for V3 RNA-based clinical G2P at 10% false positive rate AUROC = 0.83, sensitivity = 90%, specificity = 75%). The rate of agreement between DNA- and RNA-based clinical G2P was fair (kappa = 0.74, p < 0.0001), and DNA-based clinical G2P accurately predicted the plasma ESTA (AUROC = 0.86). Significant differences in the viral populations were detected when comparing inter/intra patient diversity of viral DNA with RNA sequences. CONCLUSIONS: Plasma HIV RNA or whole-blood HIV DNA V3-loop sequencing interpreted with clinical G2P is cheap and can be a good surrogate for ESTA. Although there may be differences among viral RNA and DNA populations in the same host, DNA-based G2P may be used as an indication of viral tropism in patients with undetectable plasma viremia

Reduced Rate of Diagnostic Positive Detection of JC Virus DNA in Cerebrospinal Fluid in Cases of Suspected Progressive Multifocal Leukoencephalopathy in the Era of Potent Antiretroviral Therapy

Fifty-nine human immunodeficiency virus (HIV)-infected patients with suspected progressive multifocal leukoencephalopathy and 224 controls were tested for JC virus (JCV) DNA in cerebrospinal fluid by PCR. The diagnostic positive detection rate dropped from 89.5% (95% confidence intervals of 75.5 to 103.5%) in the pre-highly active antiretroviral therapy (HAART) era to 57.5% (95% confidence intervals of 42.1 to 72.9%) in the HAART era; the specificity remained unchanged. Predictors of failure to detect JCV DNA were exposure to HAART at disease onset and higher CD4 counts

Efficient in vitro expansion of JC virus-specific CD8+ T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy

Submitted by Repositório Arca ([email protected]) on 2019-04-24T16:24:12Z No. of bitstreams: 1 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-12-23T13:30:13Z (GMT) No. of bitstreams: 2 va_Marzocchetti_Angela_etal_INI_2009.pdf: 687432 bytes, checksum: e95345d2cb16bb488cad30b236ef1523 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2019-12-23T13:30:13Z (GMT). No. of bitstreams: 2 va_Marzocchetti_Angela_etal_INI_2009.pdf: 687432 bytes, checksum: e95345d2cb16bb488cad30b236ef1523 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009Harvard Medical School. Beth Israel Deaconess Medical Center. Division of Viral Pathogenesis. Boston, MA, USA.Harvard Medical School. Beth Israel Deaconess Medical Center. Department of Neurology. Boston, MA, USA / Harvard Medical School. Beth Israel Deaconess Medical Center. Division of Viral Pathogenesis. Boston, MA, USA / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Neuroinfecções. Rio de Janeiro, RJ, Brasil.Harvard Medical School. Beth Israel Deaconess Medical Center. Division of Viral Pathogenesis. Boston, MA, USA.Harvard Medical School. Massachusetts General Hospital. Partners AIDS Research Center. Boston, MA, USA.Harvard Medical School. Massachusetts General Hospital. Partners AIDS Research Center. Boston, MA, USA.New York University. School of Medicine. New York, NY, USA.New York University. School of Medicine. New York, NY, USA.Harvard Medical School. Beth Israel Deaconess Medical Center. Department of Neurology. Boston, MA, USA / Harvard Medical School. Beth Israel Deaconess Medical Center. Division of Viral Pathogenesis. Boston, MA, USA.Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by JC virus (JCV) for which there is no cure. PML patients who have JCV-specific CD8+ cytotoxic T lymphocytes (CTL) in their blood have a better clinical outcome. We compared JCV-specific CTL responses in vitro elicited either by JCV peptide-loaded dendritic cells (DC) or by direct peptide stimulation of lymphocytes from 20 HLA A*0201+ healthy controls, HIV+ and PML patients. JCV peptide-loaded DC elicited a stronger CTL expansion in 13/15 responders. DC can induce potent JCV-specific CTL response in vitro, and may constitute a promising approach for PML immunotherapy

Determinants of survival in progressive multifocal leucoencephalopathy

BACKGROUND: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). METHODS: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. RESULTS: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count 200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. CONCLUSIONS: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML

Tenofovir discontinuation could predispose to urolithiasis in atazanavir-treated patients

No abstract availabl