Immunization with apoptotic pseudovirus transduced cells induces both cellular and humoral responses: a proof of concept study in macaques

Dendritic cells are able to present viral antigens to T-cells after uptake of apoptotic bodies derived from virus-infected cells. Immunization with virus-infected apoptotic cells was previously shown to induce HIV-specific immune responses in mice. Here we evaluate the safety and immunogenicity of immunization with activated apoptotic cells in non-human primates using autologous T-cells infected with replication defective VSV pseudotyped SIV(mac239)Δenv. Animals were immunized with γ-irradiated activated T-cells carrying the VSVenvSIV(mac239)Δenv pseudovirus. SIV Gag-specific cellular immune responses were induced as early as two weeks after the first immunization eliciting a biased IFN-γ and IL-2 response. In addition, induction of SIV Gag-specific antibody responses and high titer neutralizing activity against the SIV pseudovirus harboring a VSV-env were detected after two immunizations. The vaccinated group and a control group of Chinese rhesus macaques were intravenously challenged with pathogenic SIV(mac251.) All animals became infected, but SIV-replication was effectively suppressed (below 100 copies/ml) in several animals in both groups. However the group immunized with apoptotic cells revealed better preservation of the gut CD4(+) T-cell compartment. Viral control was inversely correlated with an early (4 weeks) but transient increase in the percentage of Ki67(+)CD4(+) peripheral blood T-cells (Spearman -0.73). We here show that immunizations with activated apoptotic lymphocytes expressing transduced SIV genes result in induction of both cellular and humoral immune responses. This study provides evidence for an immunological principle demonstrating that certain apoptotic cells can be considered as carriers of antigens directing immune responses in macaques.     

An accelerated rabies vaccine schedule based on toll-like receptor 3 (TLR3) agonist PIKA adjuvant augments rabies virus specific antibody and T cell response in healthy adult volunteers

BackgroundRabies is a fatal disease where post-exposure prophylaxis (PEP) is crucial in preventing infection. However, deaths even after appropriate PEP, have been reported. The PIKA Rabies vaccine adjuvant is a TLR3 agonist that activates B and T cells leading to a robust immune response.MethodsWe conducted a phase I, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA Rabies vaccine and an accelerated vaccine regimen. Thirty-seven subjects were randomized into 3 groups: control vaccine classic regimen, PIKA vaccine classic regimen and PIKA vaccine accelerated regimen. Subjects were followed up for safety, rabies virus neutralizing antibodies (RVNA) and T cell responses.ResultsBoth the control and PIKA Rabies vaccine were well tolerated. All adverse events (AEs) were mild and self-limiting. Seventy-five percent of subjects in the PIKA accelerated regimen achieved a RVNA titer ⩾0.5 IU/mL on day 7, compared to 53.9% in the PIKA classic regimen (p = 0.411) and 16.7% in control vaccine classic regimen (p = 0.012). The PIKA rabies vaccine elicited multi-specific rabies CD4 mediated T cell response already detectable ex vivo at day 7 after vaccination and that was maintained at day 42.ConclusionThe investigational PIKA rabies vaccine was well tolerated and more immunogenic than the commercially available vaccine in healthy adults.Clinical trial registry: The study was registered with clinicaltrials.gov NCT02657161.     

Continuous antibiotic prophylaxis reduces the risk of febrile UTI in children with asymptomatic antenatal hydronephrosis with either ureteral dilation,high-grade vesicoureteral reflux,or ureterovesical junction obstruction

BackgroundThe efficacy and utility of continuous antibiotic prophylaxis (CAP) in children with congenital antenatal hydronephrosis (ANH) is uncertain. The literature has both supportive and contradictory evidence. The growing trend not to place children with ANH on CAP has created varied clinical practice based on anecdotal individual case characteristics. Our goal was to compare individual infant characteristics between those children who were maintained on CAP to those that were not to try to determine predisposing risk factors to febrile.MethodsAll electronic medical records (EMRs) of children referred to our institution for congenital ANH over a period from 2001 to 2011 were examined. We excluded those referred for urinary tract infection (UTI) who had a history of congenital ANH. We also excluded those with incomplete records, or follow-up less than 2 years. Children were divided into two groups: those maintained on CAP (YCAP) and those not maintained on CAP (NCAP). Our primary endpoint was febrile UTI. Follow-up was at least 24 months. Demographic, perinatal and postnatal clinical data were recorded. Statistical analysis was performed using STATA Version 11.1.ResultsOf the 405 children fitting inclusion criteria, 278 (68.6%) children were maintained on CAP and 127 (31.4%) were not on CAP. The incidence of prematurity, oligohydramnios, perinatal respiratory complications, use of perinatal antibiotics, circumcision status, renal anomalies, associated medical diagnoses, and low birth weight did not differ between the two groups. Overall the incidence of febrile UTI during the follow-up period was 22.2%. The incidence of febrile UTI between the YCAP and NCAP groups was significant (YCAP = 7.9% and NCAP 18.7%, p = 0.021). Multivariate logistic regression using CAP as the dichotomous dependent variable revealed that ureteral dilation, high-grade vesicoureteral reflux (VUR), and ureterovesical junction (UVJ) obstruction were independent risk factors for febrile UTI. More specifically, children with ureteral dilation >11 mm NOT maintained on CAP had a 5.54 (OR = 5.54; CI = 3.15–7.42, p = 0.001) fold increased risk of febrile UTI compared to those maintained on CAP.ConclusionsThe presence of ureteral dilation, high grade VUR, and UVJ obstruction were independent risk factors for development of UTI in children with congenital ANH. Therefore CAP may have a significant role in reducing the risk of febrile UTI in children with ANH with those identifiable risk factors, but otherwise seems unnecessary.     

Heteroclitic peptides enhance human immunodeficiency virus-specific CD8 T cell responses

The inability of human immunodeficiency virus (HIV)-specific CD8⁺ T cells to durably control HIV replication due to HIV escape mutations and CD8⁺ T cell dysfunction is a key factor in disease progression. A few HIV-infected individuals termed elite controllers (EC) maintain polyfunctional HIV-specific CD8⁺ T cells, minimal HIV replication and normal CD4⁺ T lymphocyte numbers. Thus, therapeutic intervention to sustain or restore CD8⁺ T cell responses similar to those persisting in EC could relieve terminal dependence on antiretrovirals. Vaccination with HIV peptides is one approach to achieve this and our objective in this study was to determine whether certain HIV peptide variants display antigenic superiority over the reference peptides normally included in vaccines. Eight peptide sets were generated, each with a reference peptide and six variants harboring conservative or semi-conservative amino acid substitutions at positions predicted to affect T cell receptor interactions without affecting human class I histocompatibililty-linked antigen (HLA) binding. Recognition across peptide sets was tested with >80 HIV-infected individuals bearing the appropriate HLA alleles. While reference peptides were often the most antigenic, cross-reactivity with variants was common and in many cases, peptide variants were superior at stimulating interferon-γ production or selectively enhanced interleukin-2 production. Although such heteroclitic activity was not generalized for all individuals bearing the HLA class I allele involved, these data suggest that heteroclitic peptide variants could improve the efficacy of therapeutic peptide vaccines in HIV infection.     

Ultrasound screening for renal and urinary tract anomalies in healthy infants

BACKGROUND: Nearly 30% of childhood cases of chronic renal failure in Japan are attributed to congenital anomalies of the kidney and urinary tract (CAKUT), and the number is increasing. Urine screening at school facilitates early diagnosis and treatment of glomerulonephritis, but early screening for anomalies is currently not in practice. The authors evaluated the value of early abdominal ultrasonography screening in 1-month-old infants. METHODS: The following characteristics of kidneys were assessed: presence versus absence, size, symmetry of size, position, separation of the central echo complex (CEC), abnormal echogenicity, and other abnormal findings. The bladder and ureter were checked for abnormalities in bladder shape and wall, as well as retrovesical ureteral dilation. Criteria for abnormalities included kidney length of or=60 mm; a difference in length of left and right kidneys of 10 mm or more; and CEC separation of Society for Fetal Urology (SFU) grade 2 or higher. RESULTS: Beginning in April 1994 and continuing until September 2001, screening of 5700 1-month-old infants yielded 198 positive cases (3.5%) of CAKUT. Most frequent was abnormal CEC separation (approximately 60% of all abnormalities), followed by abnormal renal size or size asymmetry (30%). Further investigation yielded a specific diagnosis in 32 cases (0.6%) of all subjects. Most prevalent was obstructive uropathy (15 cases); 8 children underwent surgery. Small kidneys and vesicoureteral reflux were next in frequency. CONCLUSIONS: Ultrasonograpy was effective for early detection of renal and urinary tract anomalies. Ultrasound screening in early infancy may permit early treatment, that can prevent renal dysfunction.     

利用SFU开发Windows和Linux异构环境下的分布式生物信息学应用

Microsoft SFU是一个Windows环境下的高性能UNIX子系统和互操作工具，它允许Windows和UNIX计算机共享数据、安全策略和应用程序。本文通过实例，介绍如何利用SFU将Linux下的Blat软件在Windows系统中重新编译运行，并与Linux计算机共享生物序列数据库，构建异构网络环境下的分布式生物信息学应用。实践证明该技术可集成Windows和Linux的计算能力，提高计算资源的使用效率。     

Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C

BACKGROUND & AIMS: Acute hepatitis C virus (HCV) infection becomes chronic in the majority of patients. Although HCV-specific CD4 T-cell response is associated with HCV clearance, less is known about virus-specific CD8 T-cell or neutralizing antibody (nAb) responses and the role of CD4 help in their induction during acute infection. METHODS: HCV-specific CD4, CD8, and HCV pseudoparticle (HCVpp) nAb responses were monitored in acutely HCV-infected patients to define their relative contributions to viral clearance. RESULTS: Our results show that the outcome of acute hepatitis C is associated with a functional hierarchy in HCV-specific CD4 T-cell response and the scope of virus-specific, total T-cell interferon-gamma response. HCV-specific CD8 T-cell response was readily detectable in acutely HCV-infected patients regardless of virologic outcome or virus-specific CD4 T-cell response. In contrast, HCVpp-specific nAbs were readily detected in patients with chronic evolution and impaired virus-specific CD4 T-cell response but not in patients who cleared infection with robust virus-specific CD4 T-cell response. CONCLUSIONS: The outcome of acute hepatitis C is associated with efficient virus-specific CD4 T-cell response(s) without which HCV-specific CD8 T-cell and heterologous nAb responses may develop but fail to clear viremia. Furthermore, HCV-specific nAb responses may not be induced despite robust virus-specific CD4 T-cell response.