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Frontiers in Cellular and Infection... 2023Banna virus (BAV), a potential pathogen that may cause human encephalitis, is the prototype species of genus within the family , and has been isolated from a variety of...
INTRODUCTION
Banna virus (BAV), a potential pathogen that may cause human encephalitis, is the prototype species of genus within the family , and has been isolated from a variety of blood-sucking insects and mammals in Asia.
METHODS
, , and were collected overnight in Yunnan, China, during 2016-2023 using light traps. Virus was isolated from these collected blood-sucking insects and grown using (C6/36) cells. Preliminary identification of the virus was performed by agarose gel electrophoresis (AGE). The full genome sequences of the BAVs were determined by full-length amplification of cDNAs (FLAC) and sequenced using next-generation sequencing.
RESULTS
In this study, 13 strains BAV were isolated from , and . Their viral genome consisted of 12 segments of double-stranded RNA (dsRNA), and with three distinct distribution patterns. Sequence analysis showed that Seg-5 of four strains (SJ_M46, SJ_M49, JC_M19-13 and JC_C24-13) has 435 bases nucleotide sequence insertions in their ORF compared to other BAVs, resulting in the length of Seg-5 up to 2128 nt. There are 34 bases sequence deletion in Seg-9 of 3 strains (WS_T06, MS_M166 and MS_M140). Comparison of the coding sequences of VP1, VP2, VP5, VP9 and VP12 of the 13 BAV strains, the results show that VP1, VP2 and VP12 are characterised by high levels of sequence conservation, while VP9 is highly variable, under great pressure to adapt and may be correlated with serotype. While also variable, VP5 appears to be under less adaptive pressure than VP9. Additionally, phylogenetic analysis indicates that the 13 BAV strains locate in the same evolutionary cluster as BAVs isolated from various blood-sucking insects, and are clustered according to geographical distribution.
CONCLUSION
The data obtained herein would be beneficial for the surveillance of evolutionary characteristics of BAV in China and neighboring countries as well as extend the knowledge about its genomic diversity and geographic distribution.
Topics: Animals; Aedes; Ceratopogonidae; China; Coltivirus; Genome, Viral; Mammals; Phylogeny; Ticks
PubMed: 38035340
DOI: 10.3389/fcimb.2023.1283580 -
Open Forum Infectious Diseases Nov 2023To investigate the impact of the M184V/I mutation on virologic response to dolutegravir plus lamivudine (DTG + 3TC) in suppressed-switch populations, a meta-analysis was...
Virologic Response to Dolutegravir Plus Lamivudine in People With Suppressed Human Immunodeficiency Virus Type 1 and Historical M184V/I: A Systematic Literature Review and Meta-analysis.
BACKGROUND
To investigate the impact of the M184V/I mutation on virologic response to dolutegravir plus lamivudine (DTG + 3TC) in suppressed-switch populations, a meta-analysis was performed using virologic outcomes from people with human immunodeficiency virus type 1 (PWH) with and without M184V/I before DTG + 3TC switch in real-world studies identified via systematic literature review. Sensitivity analyses were performed using data from PWH with M184V/I in interventional studies identified via targeted literature review.
METHODS
Single-arm meta-analyses using common- and random-effects models were used to estimate proportions of PWH with virologic failure (VF) among real-world populations with and without M184V/I and interventional study participants with M184V/I at 24, 48, and 96 weeks.
RESULTS
Literature reviews identified 5 real-world studies from 3907 publications and 51 abstracts meeting inclusion criteria and 5 interventional studies from 1789 publications and 3 abstracts. All time points had low VF incidence in PWH with M184V/I (real-world: 1.43%-3.81%; interventional: 0.00%) and without (real-world: 0.73%-2.37%). Meta-analysis-estimated proportions (95% confidence interval) with VF were low at weeks 24, 48, and 96, respectively, for PWH with M184V/I (real-world: 0.01 [.00-.04], 0.03 [.01-.06], and 0.04 [.01-.07]; interventional: 0.00 [.00-.02], 0.00 [.00-.01], and 0.00 [.00-.03]) and without (real-world: 0.00 [.00-.02], 0.02 [.01-.04], and 0.02 [.00-.05]). One real-world study (n = 712) reported treatment-emergent M184V at VF in 1 of 652 (0.15%) PWH without prior M184V/I.
CONCLUSIONS
Results suggest that prior M184V/I has minimal impact on virologic suppression after switching to DTG + 3TC and provide reassurance when considering switching regimens in virologically suppressed PWH with incomplete treatment history or limited treatment options.
PubMed: 38033982
DOI: 10.1093/ofid/ofad526 -
Current Journal of Neurology Apr 2023
PubMed: 38011386
DOI: 10.18502/cjn.v22i2.13341 -
The Lancet. Neurology Dec 2023X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
METHODS
ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 10 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 10 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
FINDINGS
Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
INTERPRETATION
Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.
FUNDING
Astellas Gene Therapies.
Topics: Male; Child; Humans; Infant; Child, Preschool; France; Genetic Therapy; Myopathies, Structural, Congenital; Sepsis; Germany; Treatment Outcome
PubMed: 37977713
DOI: 10.1016/S1474-4422(23)00313-7 -
Cancer Gene Therapy Dec 2023Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer...
Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer (OvCa). Here, we assessed the potential of an oncolytic adenovirus expressing a variant interleukin-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, to enhance NK cell therapy efficacy in human OvCa ex vivo. Human OvCa surgical specimens were processed into single-cell suspensions and NK cells were expanded from healthy blood donors. OvCa sample digests were co-cultured ex vivo with NK cells and vIL-2 virus and cancer cell killing potential assessed in real time through cell impedance measurement. Proposed therapeutic combination was evaluated in vivo with an OvCa patient-derived xenograft (PDX) in mice. Addition of vIL-2 virus significantly enhanced NK cell therapy killing potential in treated OvCa co-cultures. Similarly, vIL-2 virus in combination with NK cell therapy promoted the best in vivo OvCa tumor control. Mechanistically, vIL-2 virus induced higher percentages of granzyme B in NK cells, and CD8+ T cells, while T regulatory cell proportions remained comparable to NK cell monotherapy in vivo. Ad5/3-E2F-d24-vIL2 virus treatment represents a promising strategy to boost adoptive NK cell therapeutic effect in human OvCa.
Topics: Humans; Animals; Mice; Female; Cytokines; Adenoviridae; Cell Line, Tumor; Ovarian Neoplasms; Cell- and Tissue-Based Therapy; Hematopoietic Stem Cell Transplantation
PubMed: 37949944
DOI: 10.1038/s41417-023-00674-3 -
Open Forum Infectious Diseases Nov 2023Data on modified Vaccinia Ankara (MVA) vaccine effectiveness against mpox in real-world settings are limited.
BACKGROUND
Data on modified Vaccinia Ankara (MVA) vaccine effectiveness against mpox in real-world settings are limited.
METHODS
We performed a retrospective cohort analysis using Cox proportional hazards regression to estimate the association between vaccination and laboratory-confirmed mpox incidence. Study subjects included all men who have sex with men seen in a sexual health clinic in Seattle, Washington, between 1 January 2020 and 31 December 2022. Subjects' receipt of vaccine and diagnosis with mpox were ascertained from public health vaccine registry and surveillance data. Analyses were adjusted for demographic factors, human immunodeficiency virus (HIV) status, and sexual risk behaviors.
RESULTS
The incidence of mpox per 100 person-years was 8.83 among patients with 0 doses, 3.32 among patients with 1 dose, and 0.78 among patients with 2 doses of MVA vaccine. Mpox diagnosis was significantly associated with age category 30-39 and 40-51 years, HIV positivity, syphilis diagnosis in the prior year, >10 sex partners in the last year, and having a clinic visit in the last year. In the multivariate model adjusting for these factors, vaccine effectiveness was 81% for 1 dose and 83% for 2 doses.
CONCLUSIONS
These data support the effectiveness of the MVA vaccine-including a single dose of the vaccine-in preventing mpox disease and highlight the appropriateness of risk factor-based prioritization of immunization early in the epidemic. The durability of MVA vaccine-induced immunity is unknown, and at-risk persons should receive 2 doses of MVA.
PubMed: 37942460
DOI: 10.1093/ofid/ofad528 -
Nature Nov 2023Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells...
Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6). Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4 T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration or are in clinical studies, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials and may influence the design and production of autologous and allogeneic cell therapies.
Topics: Humans; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Gene Expression Regulation, Viral; Genomics; Herpesvirus 6, Human; Immunotherapy, Adoptive; Infectious Encephalitis; Receptors, Chimeric Antigen; Roseolovirus Infections; Single-Cell Gene Expression Analysis; Viral Load; Virus Activation; Virus Latency
PubMed: 37938768
DOI: 10.1038/s41586-023-06704-2 -
Frontiers in Medicine 2023JC polyomavirus (JCPyV) is a ubiquitous virus that can be latent in the brain and the kidney. It is the etiologic agent responsible for progressive multifocal...
INTRODUCTION
JC polyomavirus (JCPyV) is a ubiquitous virus that can be latent in the brain and the kidney. It is the etiologic agent responsible for progressive multifocal leukoencephalopathy, a fatal, demyelinating disease of the central nervous system, and rarely causes polyomavirus nephropathy in immunocompromised kidney transplant recipients.
CASE DESCRIPTION
We present the first case of JCPyV nephropathy in a simultaneous heart-kidney transplant patient, where viral-specific hybridization staining of the kidney tissue was utilized to confirm the diagnosis. The patient was diagnosed 6 years after simultaneous heart-kidney transplantation and was treated with immunosuppression reduction and intravenous immunoglobulin.
DISCUSSION
JCPyV nephropathy should be considered in the differential diagnosis of kidney allograft injury, particularly, with suggestive light microscopy histologic features in the absence of BK polyomavirus viremia and/or viruria. In addition to obtaining JCPyV PCR in the blood, hybridization staining may have a utility in confirming the diagnosis. To date, we lack effective JCPyV-specific therapies, and prompt initiation of immunosuppression reduction remains the mainstay of treatment.
PubMed: 37928458
DOI: 10.3389/fmed.2023.1282827 -
NPJ Vaccines Nov 2023Rift Valley fever (RVF) is a zoonotic viral disease transmitted by mosquitoes and causes abortion storms, fetal malformations, and newborn animal deaths in livestock... (Review)
Review
Rift Valley fever (RVF) is a zoonotic viral disease transmitted by mosquitoes and causes abortion storms, fetal malformations, and newborn animal deaths in livestock ruminants. In humans, RVF can manifest as hemorrhagic fever, encephalitis, or retinitis. Outbreaks of RVF have been occurring in Africa since the early 20th century and continue to pose a threat to both humans and animals in various regions such as Africa, Madagascar, the Comoros, Saudi Arabia, and Yemen. The development of RVF vaccines is crucial in preventing mortality and morbidity and reducing the spread of the virus. While several veterinary vaccines have been licensed in endemic countries, there are currently no licensed RVF vaccines for human use. This review provides an overview of the existing RVF vaccines, as well as potential candidates for future studies on RVF vaccine development, including next-generation vaccines that show promise in combating the disease in both humans and animals.
PubMed: 37925544
DOI: 10.1038/s41541-023-00769-w -
Scientific Reports Oct 2023Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12...
Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12 viruses implicated in MS with respect to 17 HLA Class I alleles positively associated to MS prevalence in 14 European countries. Overall, higher V-HLA immunogenicity was associated with smaller MS-HLA effect, with human herpes virus 3 (HHV3), JC human polyoma virus (JCV), HHV1, HHV4, HHV7, HHV5 showing the strongest association, followed by HHV8, HHV6A, and HHV6B (moderate association), and human endogenous retrovirus (HERV-W), HHV2, and human papilloma virus (HPV) (weakest association). These findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to be involved in MS.
Topics: Humans; Multiple Sclerosis; Immunogenetics; Herpesvirus 6, Human; JC Virus; Europe
PubMed: 37907711
DOI: 10.1038/s41598-023-45931-5