JC Virus Infection Research Articles

Brain biopsy and pathological diagnosis for drug-associated progressive multifocal leukoencephalopathy (PML) with inflammatory reactions.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) infection. Although recognized as an AIDS complication in the 1980s, PML has emerged as a serious adverse event of immunosuppressive therapies since 2005, particularly disease-modifying drugs (DMDs) for multiple sclerosis (MS). PML can also occur in patients with collagenous diseases receiving steroid therapy or with age-related immunosuppression. In some cases, the etiology of immunosuppression remains unclear. These cases often present with early manifestations of PML, which, while common, are less well recognized, as PML was identified at more advanced stages in AIDS-related cases. Early diagnosis poses difficulty due to unfamiliar magnetic resonance (MR) images and low viral loads in cerebrospinal fluid (CSF), and brain biopsy may be conducted. This review summarizes the PML pathology identified through biopsy. Early cytopathological changes of JCV-infected cells, with the importance of dot-shaped inclusions associated with promyelocytic leukemia nuclear bodies (PML-NBs), are described. The variability of host immune responses, including PML immune reconstitution inflammatory syndrome (PML-IRIS), is addressed. The potential role of immune checkpoint inhibitors (ICIs), such as pembrolizumab, is also explored. Understanding the pathology of early PML helps to optimize diagnostic strategies and therapeutic interventions, ultimately improving prognosis.

Combination of low-dose, long-term immunoglobulin and mirtazapine is effective in progressive multifocal leukoencephalopathy caused by JC virus infection

BackgroundProgressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There’s still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case.Case presentationA patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly.ConclusionsWe demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML.

Progressive multifocal leukoencephalopathy in sarcoidosis successfully treated with pembrolizumab.

Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating disease of the central nervous system caused by JC virus infection. The disease can be seen in sarcoidosis patients without additional risk factors. Here, we present an individual with PML secondary to sarcoidosis treated with 8 doses of pembrolizumab, a Programmed Cell-Death-1 (PD-1) Immune Checkpoint Inhibitor who showed significant improvement. This report illustrates the objective clinical and radiological improvement in a patient with PML due to sarcoidosis, and suggests further study of immune checkpoint inhibitors as a potential treatment for sarcoidosis patients with PML.

Investigate the Relationship Between the Presence of JCV DNA and the Immunohistochemical Expression of CK2 0, CK7, and CDX2 in Colorectal Cancer

Abstract Background: Globally, colorectal cancer (CRC) is the most common malignancy and has a high fatality rate. Early childhood the John Cunningham virus or JC virus (JCV) infection persists throughout life and has been linked through multiple routes to colorectal cancer. The expression of cytokeratins 7 (CK7), 20 (CK20), and CDX2 have been investigated in a variety of primary and metastatic carcinomas, and their patterns of expression may be used to determine the site of origin of metastatic carcinomas. Objectives: The aim is to assess the relationship between JCV DNA and tumor markers (CK7, CK20, and CDX2) in patients with colorectal cancer, this study was carried out. Materials and Methods: Ninety CRCs (45 of which were squamous cell carcinomas and 45 of which were adenocarcinomas) had their paraffin sections randomly chosen, extracted, and immunostained for CK7, CK20, CDX2, and for the detection of JCV DNA by real-time (PCR). Results: JCV DNA was detected in 22 (24.4%) of AD-CRC and 24 (26.7%) of SCC-CRC (P = 0.004). The presence of JCV was significantly correlated with tumor stages (P = 0.04) and age categories (P = 0.05). Moreover, JCV presence was significantly correlated with all studied tumor markers (P < 0.05). Conclusion: JCV might play a role in the development of colorectal cancer, and CDX2, which is highly specific and sensitive as markers of colorectal origin should be helpful in the detection of intestinal adenocarcinomas.

Real-Life Experience of Safety Profile of a Rituximab Biosimilar (Reditux®) in Patients at a Rheumatology Center in India

Abstract Aim: The aim of this study was to study the safety profile of a rituximab (RTX) biosimilar Reditux® in patients of rheumatological disorders at a tertiary care hospital in North India. Methodology: An observational study was carried out to ascertain the safety of RTX in rheumatology patients. A total of 60 patients initiated on RTX were followed up for a mean duration of 14 months for adverse events. Results: A total of seven mild infusion reactions were recorded during the first infusion of RTX. Eighteen infective events were recorded including a case of extrapulmonary tuberculosis (TB), three cases of hepatitis B virus (HBV) reactivation, four cases of herpes zoster, and a fatal case of disseminated varicella infection. There were no cases of JC virus infection or malignancies in our study. Conclusion: This study highlights a much higher incidence of infections following the use of RTX in India as compared to international studies published so far. We also observed a higher rate of reactivation of HBV, varicella zoster virus, and TB in our cohort. This emphasizes the need for revising protocols for screening, vaccination, and chemoprophylaxis for chronic infections in countries with high burden of infections.

Revisiting JC virus and progressive multifocal leukoencephalopathy.

Since its definition 65years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.

Human neurotropic polyomavirus, JC virus, late coding region encodes a novel nuclear protein, ORF4, which targets the promyelocytic leukemia nuclear bodies (PML-NBs) and modulates their reorganization

We previously reported the discovery and characterization of two novel proteins (ORF1 and ORF2) generated by the alternative splicing of the JC virus (JCV) late coding region. Here, we report the discovery and partial characterization of three additional novel ORFs from the same coding region, ORF3, ORF4 and ORF5, which potentially encode 70, 173 and 265 amino acid long proteins respectively. While ORF3 protein exhibits a uniform distribution pattern throughout the cells, we were unable to detect ORF5 expression. Surprisingly, ORF4 protein was determined to be the only JCV protein specifically targeting the promyelocytic leukemia nuclear bodies (PML-NBs) and inducing their reorganization in nucleus. Although ORF4 protein has a modest effect on JCV replication, it is implicated to play major roles during the JCV life cycle, perhaps by regulating the antiviral response of PML-NBs against JCV infections and thus facilitating the progression of the JCV-induced disease in infected individuals.

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies.

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. 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). 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. 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.

JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient.

JC virus (JCV) is common among healthy individuals and remains latent but may be reactivated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML). Here, we present a rare case of PML caused by JC virus infection in a previously healthy and immunocompetent patient. A 67-year-old female without any disease history was admitted after presenting with rapidly progressive dementia. The preoperative diagnosis was progressive multifocal leukoencephalopathy, and corticosteroid treatment did not improve the symptoms. Brain lesions were surgically sampled, and JCV infection was confirmed by high-throughput DNA gene detection. This patient received a combined treatment of mirtazapine, mefloquine, and traditional Chinese herbs, and had stabilization of the disease on followed-up. Although it is a rare, this case demonstrates that JC virus infection within the brain occurs in apparently healthy people. This case may increase our understanding of virus infection when facing the coronavirus epidemic in recent years, considering that similar medications were used.

Final Clinical Outcomes from a Phase 2 Trial of Posoleucel, an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Clinically Significant Viral Infections Post-HCT

Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV). Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible. Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples. Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus. Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome. TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution. Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Kidney Transplant Recipients with JC Virus Infection Have Decreased Function of the Transplanted Kidney

Kidney Transplant Recipients with JC Virus Infection Have Decreased Function of the Transplanted Kidney

A human-derived 3D brain organoid model to study JC virus infection.

Progressive multifocal leukoencephalopathy (PML) is a frequent neurological complication in immunosuppressed patients. PML is caused by the JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination which lead to neurological dysfunction. The pathogenesis of PML is poorly understood due to the lack of in vitro or animal models to study mechanisms of disease as the virus most efficiently infects only human cells. We developed a human-derived brain organotypic system (also called brain organoid) to model JCV infection. The model was developed by using human-induced pluripotent stem cells (iPSC) and culturing them in 3D to generate an organotypic model containing neurons, astrocytes, and oligodendrocytes which recapitulates aspects of the environment of the human brain. We infected the brain organoids with the JCV MAD4 strain or cerebrospinal fluid of a patient with PML. The organoids were assessed for evidence of infection by qPCR, immunofluorescence, and electron microscopy at 1, 2, and 3 weeks post-exposure. JCV infection in both JCV MAD4 strain and PML CSF-exposed brain organoids was confirmed by immunocytochemical studies demonstrating viral antigens and electron microscopy showing virion particles in the nuclear compartment of oligodendrocytes and astrocytes. No evidence of neuronal infection was visualized. Infection was also demonstrated by JCV qPCR in the virus-exposed organoids and their media. In conclusion, the brain organoid model of JCV infection establishes a human model suitable for studying the mechanisms of JCV infection and pathogenesis of PML and may facilitate the exploration of therapeutic approaches.

Posoleucel (ALVR105), an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Viral Infections Post-HCT: Results from an Open-Label Cohort of a Phase 2 Trial

Posoleucel (ALVR105), an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Viral Infections Post-HCT: Results from an Open-Label Cohort of a Phase 2 Trial

Central nervous system disease with JC virus infection in adults with congenital HIV.

The aim of this study was to describe the natural history of individuals with congenital HIV who develop JC virus (JCV) infection of the central nervous system (CNS). We retrospectively evaluated individuals with congenital HIV who met criteria for progressive multifocal leukoencephalopathy (PML) or JCV granule cell neuronopathy (JCV GCN) at three major healthcare centres in the northeast USA. Data on adherence to combined antiretroviral therapy (cART), neurologic symptoms, serum markers of immunity and HIV infection, cerebrospinal fluid (CSF) analyses, radiographic features, modified Rankin Scale (mRS) scores and survival were collected from the electronic medical record up to a censoring date of 1 August 2020. Among 10 adults with congenitally acquired HIV, nine were diagnosed with definitive PML and one was diagnosed with probable JCV GCN. Individuals presented at the time of their PML or JCV GCN diagnosis with a mean mRS of 2.0 (standard deviation 1.0). A premorbid mRS was documented for six patients and was zero in all cases. The most common risk factor was confirmed cART nonadherence in nine individuals. Five individuals with PML and one with JCV GCN died, with a latency from symptom onset to death of approximately 3 months for three individuals, and approximately 2 years for the remaining two. Youth-adulthood transition is a high-risk point for dropping off from medical care. The study of this timepoint in people living with HIV could help inform effective care in these individuals.

AIDS-related progressive multifocal leukoencephalopathy.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV). METHODS: We described the profile of laboratory-confirmed PML cases among AIDS patients. RESULTS: A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³. CONCLUSIONS: Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.

CLINICAL COURSE OF SCHIMKE IMMUNO-OSSEOUS DYSPLASIA AFTER KIDNEY TRANSPLANTATION

Schimke immuno-osseous dysplasia (SIOD) is one of the rare causes of steroid-resistant nephrotic syndrome. Extra-renal symptoms of this autosomal recessive disease include spondyloepiphyseal dysplasia, disproportional growth failure and defective cellular immunity. Kidney transplantation (KT) is indicated in these patients when their kidney problems progress to end-stage renal disease (ESRD). Due to the rarity of this condition, clinical course of SIOD after KT is not well known yet. Here we present our experience of SIOD after KT. Since 2014 three children with focal segmental glomerulosclerosis (FSGS) confirmed by biopsy were diagnosed as SIOD through genetic analysis. Onset age of proteinuria was 7, 5, 3 years, respectively. All of them had disproportional growth failure and typical facial feature. They reached ESRD in about two years after diagnosis of proteinuria. At their age of 9, 7, 9 years, these patients had living donor KT from their parents. After KT they suffered from multiple infections. Case 1 had PCP pneumonia requiring ventilator care 2 months after KT, then in 3 months disseminated adenovirus infection occurred along with CMV, EBV, and JC virus infection. The patient succumbed to the infection in 2 months despite aggressive management. Case 2 had CMV infection and PCP pneumonia after 3 months of KT. She suffered from skin infection and otitis. Case 3 suffered from respiratory failure due to CMV infection after 5 months of KT. Recurrent hospitalization was required due to various infections. Allograft has survived for 3.5 years in case 3 despite low-dose tacrolimus single medication (< 5ng/mL), but case 1 lost his graft function along with disseminated adenovirus infection. Case 2 had graft failure after 5 years of KT from acute rejection, probably due to insufficient dosage of tacrolimus and poor compliance. As Extra-renal presentation case 1 had renal vein thrombosis extended to IVC and pulmonary hypertension before KT, lowering his oxygen saturation to 80-90% in room air. Case 2 had severe developmental dysplasia of the hip requiring orthopedic surgery at the age of 5. She had sitting height and leg length ratio of 0.96, vertebral flattening and lordosis on spine x-ray suggesting spondyloepiphyseal dysplasia. After KT she suffered constant headache and Moyamoya syndrome was dignosed. She had an encephaloduroarteriosynangiosis when she was 10yrs 4month old. Case 3 suffered from spontaneous bacterial peritonitis and recurrent rhabdomyolysis along with neutropenia and thrombocytopenia before KT. In three years of KT his neutropenia and thrombocytopenia aggravated and bone marrow study suggested aplastic anemia. Hematopoietic stem cell transplantation is under consideration. In summary, SIOD is a rare systemic disease presenting as FSGS. While KT is indicated for their ESRD, their extra-renal symptoms progress regardless of KT. With its defective cellular immunity multiple infections complicate the clinical course after KT in SIOD.

Progressive multifocal leucoencephalopathy as a manifestation of immune reconstitution inflammatory syndrome in a patient with HIV infection: a case report

Immune reconstitution inflammatory syndrome (IRIS) is defined as paradoxical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy (ART) in HIV-infected patients. IRIS results from restored immunity to specific infectious or non-infectious antigens. Immune reconstitution following initiation of ART may lead to activation of an inflammatory response to detectable or latent JC virus (JCV) infection, an etiological agent of progressive multifocal leucoencephalopathy (PML). We present an interesting case of IRIS manifesting as PML in a newlydiagnosed HIV-infected patient started on ART.

Adipocyte Plasma Membrane Protein (APMAP) promotes JC Virus (JCPyV) infection in human glial cells

The demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the human polyomavirus, JCPyV, under conditions of prolonged immunosuppression. Initial infection is asymptomatic, and the virus establishes lifelong persistence in the host. Following the loss of immune surveillance, the virus can traffic to the central nervous system and infect oligodendrocytes to cause demyelination and PML. The mechanisms involved in glial cell infection are not completely understood. In a screen for N-glycosylated proteins that influence JCPyV pathology, we identified Adipocyte Plasma Membrane Associated Protein (APMAP) as a host cell modulator of JCPyV infection. The removal of APMAP by small interfering siRNA as well as by CRISPR-Cas9 gene editing resulted in a significant decrease in JCPyV infection. Exogenous expression of APMAP in APMAP knockout cell lines rescued susceptibility to infection. These data suggest that virus infection of glial cells is dependent on APMAP.

Atypical Spectrum of JC Virus Infection Syndrome: Report of Three Cases (1997)

Atypical Spectrum of JC Virus Infection Syndrome: Report of Three Cases (1997)

Impact of HLA Class I Allele Mismatch on Viral Infection within 100 Days after Cord Blood Transplantation

Introduction: Viral infections occur more frequently in cord blood transplantation (CBT) than in transplantation of other stem cell sources, and they are often fatal. Thus, it is important to determine the predictors of viral infection to improve CBT outcomes. We hypothesized that incompatibility of human leukocyte antigen (HLA) class I can increase susceptibility to viral infections because donor HLA-restricted naïve cytotoxic T cells cannot recognize recipient infected cells properly in the early term after CBT. Herein, we focused on the impact of HLA class I incompatibility on viral infection within 100 days after CBT. Patients and Methods: We retrospectively analyzed 121 patients who underwent 126 CBT procedures at Kyoto University Hospital from February 2003 to January 2019. Viral infection was defined as infection of recipient somatic cells by viruses detected via pathology or molecular biology and confined to those specific for an immunocompromised condition. Cytomegalovirus (CMV) antigenemia was distinguished from viral infections, because in such cases, the infected cells are donor-derived cells. Characteristics were compared between two groups using Fisher's test. The incidences of viral infection, CMV antigenemia, and steroid use for pre-engraftment immune reaction, engraftment syndrome, and acute graft-versus-host disease (aGVHD) together (PIR/ES/aGVHD) were calculated considering death and relapse as competing events, and they were compared using Gray's test. Fine-Gray proportional hazards models were used for univariate and multivariate analyses to evaluate the effects of variables on outcome. Survival was estimated using the Kaplan-Meier method. Non-relapse mortality was estimated using Gray's method. Results: The median patient age was 47 (range, 19-68) years, and 69 patients were male. The underlying diseases were acute myeloid leukemia (n=53), acute lymphoblastic leukemia (n=17), myelodysplastic syndromes (n=17), anaplastic anemia (n=6), non-Hodgkin lymphoma (n=20), and others (n=9). Regarding the CBT protocol, 44 patients received myeloablative conditioning and 83 patients received a calcineurin inhibitor and mycophenolate mofetil for GVHD prophylaxis. We identified 50 virus infections in 42 transplants within 100 days after transplantation, including 7 human herpesvirus 6 infections, 14 CMV infections, 26 BK virus, JC virus, and adenovirus infections, 2 varicella-zoster virus infections, and 1 unknown virus infection. Univariate analysis showed that HLA-A and HLA-C allele mismatches in the GVH direction were associated with a significantly higher incidence of viral infection (mismatch vs. match; HLA-A: 42.7% vs. 25.8%, HR 1.86, P=0.049; HLA-C: 43.9% vs. 17.6%, HR 2.94, P=0.015; Figure 1A). Moreover, 3/6 or more HLA class I allele mismatch in the GVH direction was associated with a significantly higher viral infection incidence (50.0% vs. 26.9%, HR 2.29, P=0.010; Figure 1B), but not with CMV antigenemia (65.8% vs. 70.1%, HR 0.95, P=0.82). These patients with HLA class I mismatches showed no increase in steroid use for PIR/ES/aGVHD (70.4% vs. 64.2%, P=0.53) or prophylactic antiviral drug therapy (62.5% vs. 65.7%, P=0.84). Regarding HLA class II mismatches, HLA-DR mismatch in the GVH direction was not associated with viral infection (34.1% vs. 32.6%, HR 1.13, P=0.72). Univariate analysis showed that lymphoid neoplasm (P&lt;0.01), no use of cytarabine for conditioning (P=0.035), fludarabine and melphalan use for conditioning (P=0.043 and 0.075, respectively), and second or subsequent transplant (P=0.067) were associated with a higher incidence of viral infection. Multivariate analysis showed that HLA class I mismatches and lymphoid neoplasm remained significant factors for viral infection (P=0.035 and &lt;0.01, respectively). Regarding post-CBT outcomes, 5-year overall survival (OS) and non-relapse mortality (NRM) with landmark analysis at 100 days were inferior in patients with viral infection (OS: 66.5% vs. 73.6%, P=0.35; NRM: 14.6% vs. 4.6%, P=0.11). Conclusion: HLA class I allele mismatch, including HLA-C mismatch, was significantly associated with viral infection within 100 days of CBT. Our findings suggest the importance of HLA class I genotype compatibility, including HLA-C compatibility, for CBT. Graft matching can reduce the incidence of viral infection and thus improve outcomes. Figure 1 Disclosures Kanda: Chugai: Honoraria; Otsuka: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Meyers Squib: Honoraria; Kyowa Hakko Kirin: Honoraria; NextGeM Incorporation: Patents &amp; Royalties: 2019-011392; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Astellas: Honoraria. Takaori-Kondo:Chugai: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding.