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Experimental and Clinical... Jan 2020The main function of HLA is to present antigens to lymphocytes and to initiate specific immune responses. Autoimmune, viral, allergic, and neurologic diseases have been...
OBJECTIVES
The main function of HLA is to present antigens to lymphocytes and to initiate specific immune responses. Autoimmune, viral, allergic, and neurologic diseases have been found to be related to HLA molecules. In renal transplant, the main target of the recipient's immune system is the HLA molecules on the surface of donor cells. HLA also plays a role in the development of an immune response to viral infections. After renal transplant, BK virus infections may occur due to immunosuppression. Here, we investigated the relationship between HLA and BK virus in renal transplant recipients.
MATERIALS AND METHODS
This retrospective study investigated HLA-A, HLA-B, and HLA-DR tissue typing before renal transplant. DNA was isolated from whole blood, and tissue typing tests were performed based on polymerase chain reaction. Patients were tested for BK virus posttransplant using DNA isolated from urine and/or plasma samples.
RESULTS
We found HLA-B*13 allele to be a protective factor (P < .049; odds ratio: 0.131; 95% confidence interval, 0.017-1.029) and HLA-DRB1*03 allele to be a possible risk factor (P < .029; odds ratio: 2.521; 95% confidence interval, 1.157-5.490) against BK virus. No significant relationships were found between BK virus and age, sex, donor type, and HLA mismatch.
CONCLUSIONS
HLA class I molecules are known to be effective against viruses with the help of cytotoxic T cells. HLA-B*13 alleles within the HLA class I molecules were identified as protective factors against BK virus. HLA class II is associated with CD4-positive T cells that help secrete immune system cytokines, playing a role in stimulating and suppressing the immune system. We demonstrated that HLA-DRB1*03 allele could be a risk factor against BK virus. This allele may be associated with immunomodulatory cytokine secretion of the immune system.
Topics: BK Virus; DNA, Viral; Female; Gene Frequency; HLA Antigens; Host-Pathogen Interactions; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Opportunistic Infections; Polyomavirus Infections; Retrospective Studies; Treatment Outcome; Tumor Virus Infections; Viral Load
PubMed: 32008495
DOI: 10.6002/ect.TOND-TDTD2019.O24 -
Frontiers in Medicine 2023BK virus infection after kidney transplantation can negatively impact the prognosis of patients. However, current risk factor analyses primarily focus on BK virus...
BACKGROUND
BK virus infection after kidney transplantation can negatively impact the prognosis of patients. However, current risk factor analyses primarily focus on BK virus nephropathy, while BK viruria and BK viruria progressing to BK viremia receive less attention. This study aims to analyze the risk factors associated with BK viruria and BK viruria progressing to BK viremia in recipients of donation after cardiac death (DCD), with the goal of facilitating early intervention.
METHODS
Donor characteristics and clinical data of recipients before and after transplantation were evaluated, and logistic univariate and multivariate analyses were performed to determine the risk factors associated with BK viruria and the progression of BK viruria to BK viremia. Additionally, machine learning techniques were employed to identify the top five features associated with BK viruria evolving into BK viremia.
RESULTS
During a median follow-up time of 1,072 days (range 739-1,418), 69 transplant recipients (15.6% incidence rate) developed BK viruria after transplantation, with 49.3% of cases occurring within 6 months post-transplantation. Moreover, 19 patients progressed to BK viremia. Donor age [OR: 1.022 (1.000, 1.045), = 0.047] and donor procalcitonin (PCT) levels [0.5-10 ng/ml; OR: 0.482 (0.280, 0.828), = 0.008] were identified as independent risk factors for BK viruria. High BK viruria [OR: 11.641 (1.745, 77.678), = 0.011], recipient age [OR: 1.106 (1.017, 1.202), = 0.018], and immunoinduction regimen [ATG; OR: 0.063 (0.006, 0.683), = 0.023] were independent risk factors for BK viruria progressing to BK viremia. Machine learning analysis confirmed the importance of high BK viruria, recipient age, and immunoinduction regimen (ATG) in predicting the progression of BK viruria to BK viremia.
CONCLUSION
The development and progression of BK virus in DCD kidney transplant recipients is influenced by multiple factors. Early intervention and treatment could potentially extend the lifespan of the transplanted organ.
PubMed: 37502357
DOI: 10.3389/fmed.2023.1181743 -
EBioMedicine Nov 2021A barrier to HIV-1 cure rests in the persistence of proviral DNA in infected CD4+ leukocytes. The high HIV-1 mutation rate leads to viral diversity, immune evasion, and...
BACKGROUND
A barrier to HIV-1 cure rests in the persistence of proviral DNA in infected CD4+ leukocytes. The high HIV-1 mutation rate leads to viral diversity, immune evasion, and consequent antiretroviral drug resistance. While CRISPR-spCas9 can eliminate latent proviral DNA, its efficacy is limited by HIV strain diversity and precision target cell delivery.
METHODS
A library of guide RNAs (gRNAs) designed to disrupt five HIV-1 exons (tat/rev/gp41) was constructed. The gRNAs were derived from a conseensus sequence of the transcriptional regulator tat from 4004 HIV-1 strains. Efficacy was affirmed by gRNA cell entry through transfection, electroporation, or by lentivirus or lipid nanoparticle (LNP) delivery. Treated cells were evaluated for viral excision by monitoring HIV-1 DNA, RNA, protein, and progeny virus levels.
FINDINGS
Virus was reduced in all transmitted founder strains by 82 and 94% after CRISPR TatDE transfection or lentivirus treatments, respectively. No recorded off-target cleavages were detected. Electroporation of TatDE ribonucleoprotein and delivery of LNP TatDE gRNA and spCas9 mRNA to latently infected cells resulted in up to 100% viral excision. Protection against HIV-1-challenge or induction of virus during latent infection, in primary or transformed CD4+ T cells or monocytes was achieved. We propose that multi-exon gRNA TatDE disruption delivered by LNPs enables translation for animal and human testing.
INTERPRETATION
These results provide "proof of concept' for CRISPR gRNA treatments for HIV-1 elimination. The absence of full-length viral DNA by LNP delivery paired with undetectable off-target affirms the importance of payload delivery for effective viral gene editing.
FUNDING
The work was supported by the University of Nebraska Foundation, including donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, and individual donor support from the Frances and Louie Blumkin Foundation and from Harriet Singer. The research received support from National Institutes of Health grants T32 NS105594, 5R01MH121402, 1R01Al158160, R01 DA054535, PO1 DA028555, R01 NS126089, R01 NS36126, PO1 MH64570, P30 MH062261, and 2R01 NS034239.
Topics: CRISPR-Cas Systems; Cell Line; Conserved Sequence; Exons; Fluorescent Antibody Technique; Gene Editing; Gene Targeting; Genes, Reporter; Genetic Therapy; Genetic Vectors; Genome, Viral; HIV Infections; HIV-1; Humans; Liposomes; Macrophages; Nanoparticles; Proviruses; RNA Interference; RNA, Messenger; rev Gene Products, Human Immunodeficiency Virus; tat Gene Products, Human Immunodeficiency Virus; RNA, Guide, CRISPR-Cas Systems
PubMed: 34774454
DOI: 10.1016/j.ebiom.2021.103678 -
World Journal of Transplantation Mar 2024Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of... (Review)
Review
Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes. Hence, prevention, early detection, and prompt treatment of such infe ctions are of paramount importance. Among all viral infections, herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus), hepatitis B and C viruses, BK polyomavirus, and respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus) are common in kidney transplant recipients. These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome. Recent advances in tech nology and antiviral therapy have improved management strategies in screening, monitoring, adoption of prophylactic or preemptive therapy and precise trea tment in the immunocompromised host, with significant impact on the outcome. This review discusses the etiology, screening and monitoring, diagnosis, pre vention, and treatment of common viral infections in pediatric renal transplant recipients.
PubMed: 38576764
DOI: 10.5500/wjt.v14.i1.89978 -
Scientific Reports Jan 2023BK (BKPyV) and JC (JCPyV) polyomavirus infections are commonly subclinical and known infrequently to cause serious clinical diseases. Longitudinal follow-up studies...
BK (BKPyV) and JC (JCPyV) polyomavirus infections are commonly subclinical and known infrequently to cause serious clinical diseases. Longitudinal follow-up studies regarding JCPyV and BKPyV serological outcomes are scanty. We analyzed JCPyV and BKPyV IgG-antibodies in 327 pregnant women and their 132 spouses, enrolled in the longitudinal Finnish Family HPV cohort at Turku University Hospital, Finland. Blood samples taken at baseline, and at 12-, 24-, and 36-month follow-up visits were analyzed for capsid protein VP1-antibodies using multiplex serology. Seroprevalence was constant for both BKPyV and JCPyV across the follow-up, varying between 95-99% and 59-68%, respectively, in women and between 96-97% and 66-72%, respectively, in their spouses. Seroconversion to BKPyV and JCPyV was detected in 15% and 18% of the women and in 13% and 19% of the men, respectively. Waning of BKPyV and JCPyV antibodies was infrequent, present in only 5% of the women (both viruses) and in 1.5% of the male spouses (only BKPyV). The number of lifetime sexual partners (p = 0.038) was lower among JCPyV seropositive men. To conclude, seropositivity to BKPyV and JCPyV is common among marital couples in Finland, with only slight differences between genders. In men, the sexual behavior might be associated with JCPyV seroprevalence.
Topics: Humans; Male; Female; Pregnancy; Finland; Seroepidemiologic Studies; Spouses; JC Virus; BK Virus; Polyomavirus Infections
PubMed: 36650213
DOI: 10.1038/s41598-023-27850-7 -
Food and Environmental Virology Sep 2022The objective of this study was to compare human adenoviruses (HAdVs) genome and infectivity, polyomaviruses (JC and BK) genome (JCPyVs) and (BKPyVs), Pepper Mild Mottle...
The objective of this study was to compare human adenoviruses (HAdVs) genome and infectivity, polyomaviruses (JC and BK) genome (JCPyVs) and (BKPyVs), Pepper Mild Mottle Virus (PMMoV) genome and infectivity, and infectious bacteriophages as viral indices for sewage and water samples. One hundred and forty-four samples were collected from inlets and outlets of water and wastewater treatment plants (WTPs), and WWTPs within Greater Cairo from October 2015 till March 2017. Two methods of viral concentration [Aluminium hydroxide (Al(OH)) precipitation method and adsorption-elution technique followed by organic flocculation method] were compared to determine which of them was the best method to concentrate viruses from sewage and water. Although samples with only one litre volume were concentrated using Al(OH) precipitation method and the same samples with larger volumes (5-20 L) were concentrated using the adsorption-elution technique followed by the organic flocculation method, a non-significant difference was observed between the efficiency of the two methods in all types of samples except for the drinking water samples. Based on the qualitative prevalence of studied viruses in water and wastewater samples, the number of genome copies and infectious units in the same samples, resistance to treatment processes in water and wastewater treatment plants, higher frequency of both adenoviruses and PMMoV genomes as candidate viral indices in treated sewage and drinking water was observed. The problem of having a viral genome as indices of viral pollution is that it does not express the recent viral pollution because of the longer survivability of the viral genome than the infectious units in water and wastewater. Both infectious adenovirus and infectious phiX174 bacteriophage virus showed similar efficiencies as indices for viral pollution in drinking water and treated sewage samples. On the other hand, qualitative detection of infectious PMMoV failed to express efficiently the presence/absence of infectious enteric viruses in drinking water samples. Infectious adenoviruses and infectious bacteriophage phiX174 virus may be better candidates than adenoviruses genome, polyomaviruses genome, and PMMoV genome and infectivity as viral indices for water and wastewater.
Topics: Adenoviruses, Human; Drinking Water; Humans; Sewage; Tobamovirus; Wastewater; Water Microbiology
PubMed: 35713790
DOI: 10.1007/s12560-022-09525-0 -
Journal of Global Infectious Diseases 2022BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ...
INTRODUCTION
BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection.
METHODS
This retrospective case-control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology.
RESULTS
Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0-858) days. Survival was significantly lower in the cases (42.9% vs. 61%, < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning ( = 0.04), residual disease at the time of transplant in malignant conditions ( = 0.001), lower CD34 dose ( = 0.006), presence of acute graft versus host disease (GVHD, < 0.001), reactivation of cytomegalovirus infection ( < 0.001), and presence of bacterial urinary tract infection (UTI) ( < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD ( = 0.041), bacterial UTI ( < 0.001), and residual disease ( = 0.009) at HCT as significant risk factors for BKPyV-HC.
CONCLUSIONS
Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.
PubMed: 35418731
DOI: 10.4103/jgid.jgid_139_21 -
Intervirology 2021Members of the Polyomaviridae family, BK virus (BKV), and John Cunningham virus (JCV) are linked to polyomavirus-associated nephropathy-associated transplant rejection...
BACKGROUND
Members of the Polyomaviridae family, BK virus (BKV), and John Cunningham virus (JCV) are linked to polyomavirus-associated nephropathy-associated transplant rejection in immunodeficient patients.
OBJECTIVE
The aim of the study was to evaluate the prevalence of BKV and JCV in immunocompetent individuals in the north of Iran.
METHODS
Ninety-one urine samples were obtained from renal transplant recipients with a mean age of 39.78 ± 11.19 years. A healthy control group of 65 volunteers with an average age of 40.32 ± 10.7 years also contributed. After DNA extraction, positive cases were detected through PCR. Genotyping was done by alignment and phylogenetic tree construction of the VP1 region against all known JCV and BKV genotypes.
RESULTS
The prevalence of BKV and JCV was 15.38 and 19.78%, respectively. JCV was detected in 7.69% of the control group. The prevalence of the BKV between the case and control groups was significant (p < 0.0001). There was no significant association between BKV and JCV and duration of dialysis (p > 0.05). Overall, 62.16% of JCV cases were genotype I. Besides, genotype II was dominant within patients with BKV-positive patients.
DISCUSSION
The results obtained here show a relatively lower prevalence of BKV and JCV in immunocompromised renal transplant receivers and healthy control than those reported from other areas in Iran. JCV genotyping was evaluated for the first time in Iran. Genotype I for JCV and genotype II for BKV were dominant genotypes in the north of Iran.
Topics: Adult; BK Virus; Caspian Sea; DNA, Viral; Humans; JC Virus; Kidney Transplantation; Middle Aged; Phylogeny; Polyomavirus Infections; Transplant Recipients; Tumor Virus Infections
PubMed: 33596566
DOI: 10.1159/000513369 -
Frontiers in Medicine 2023Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively...
BACKGROUND
Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective.
METHODS
We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and -specific memory T-cells. We also present the method for selecting the best donors for CD45RA cells in each case and the procedure to isolate and store these cells.
RESULTS
The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes.
CONCLUSION
The use of familial CD45RA T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.
PubMed: 36844219
DOI: 10.3389/fmed.2023.1083215 -
Indian Journal of Nephrology 2022Polyomavirus nephropathy (PVN) is a known complication of renal transplantation due to the reactivation of latent BK virus (BKV) infection. Viral replication is usually...
Polyomavirus nephropathy (PVN) is a known complication of renal transplantation due to the reactivation of latent BK virus (BKV) infection. Viral replication is usually confined to tubules. However, in severe viremia and late stages of PVN, it can involve glomerular parietal epithelial cells. Glomerular involvement by BKV can cause crescent formation and may lead to graft failure. We describe a relatively rare case of PVN with glomerular involvement and crescent formation in a 52-year-old male who had undergone a transplant 16 months ago. Despite the stoppage of immunosuppression, graft failure occurred eventually. Interestingly, we observed the intense positivity for IgG and c4d in the Bowman capsule on immunofluorescence. Observation of such positivity along Bowman capsule in renal biopsies with a limited number of glomeruli should alert pathologists to do a vigilant search of BKV inclusion and perform immunohistochemistry for SV 40 large T antigen.
PubMed: 36704584
DOI: 10.4103/ijn.ijn_336_21