Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.

The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40-60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3's effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15-25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.

Esophageal tuberculosis mimicking submucosal tumor: A rare case.

INTRODUCTION: Esophageal tuberculosis (ET) is a rare form of infectious esophagitis. Here, we present a case of primary ET in an immunocompetent patient with dysphagia. CASE PRESENTATION: Esophagogastroduodenoscopy (EGD) revealed a submucosal tumor (SMT)-like lesion in the distal esophagus. Subsequent endoscopic ultrasonography (EUS) showed ulceration, esophageal wall discontinuities, thickening, and hypoechoic masses. Histopathological analysis confirmed a tuberculoid granuloma within the lesion. Imaging studies ruled out pulmonary tuberculosis and lymph node involvement. The patient received six months of antituberculosis treatment, resulting in significant improvement on follow-up EGD. DISCUSSION: ET is often misdiagnosed due to its rarity and nonspecific symptoms. In this case, the clinical presentation of dysphagia, combined with the characteristic findings on EGD and EUS, led to the diagnosis of primary esophageal tuberculosis. CONCLUSION: Prompt consideration of ET in dysphagia patients with SMT-like lesions and timely initiation of appropriate antituberculosis treatment can improve clinical outcomes and help avoid unnecessary surgeries.

NLRC4 gain-of-function variant is identified in a patient with systemic lupus erythematosus.

NLRC4 gain-of-function variants are known to cause various autoinflammatory phenotypes, including familial cold autoinflammatory syndrome (FCAS4) and NLRC4 macrophage activation syndrome (NLRC4-MAS). However, to date, no study has linked NLRC4 gain-of-function variants to systemic lupus erythematosus (SLE). In this study, we identified a novel NLRC4 W655S variant in an SLE patient and her son, who had neonatal lupus complicated with macrophage activation syndrome. Our in vitro experiments demonstrated that the W655S NLRC4 increased ASC speck formation and mature IL-1ß secretion compared to the wild-type NLRC4. In addition, the patient had elevated levels of IL-1ß and IL-18 in both serum and PBMCs. RNA sequencing showed that NF-κB and interferon signaling pathways were significantly activated in the patient compared to healthy controls. Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. In conclusion, our study identified the NLRC4 W655S variant in a patient with SLE. This is the first report linking inflammasomopathy to monogenic SLE. Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease.

Appendiceal bleeding: A case report.

BACKGROUND: Acute lower gastrointestinal bleeding is common in clinical practice, and the colon is responsible for the majority of cases. However, appendiceal bleeding is an extremely rare cause. Appendiceal bleeding due to vascular diseases, such as angiodysplasia and Dieulafoy's lesion, may result in massive lower gastrointestinal bleeding. Appendectomy is a reliable and effective option for treatment. CASE SUMMARY: A 32-year-old male presented to our hospital with hematochezia that had lasted for 6 h, with approximately 600-800 mL bloody stools and loss of consciousness for a few seconds. Persistent bleeding from the orifice of the appendix was observed by colonoscopy. Following the new diagnosis of appendiceal bleeding, the patient was treated by an emergency laparoscopic appendectomy. Finally, the patient was pathologically diagnosed with appendiceal Dieulafoy's lesion. The patient was uneventfully discharged, and follow-up 2 wk later showed no evidence of rebleeding. CONCLUSION: Although appendiceal bleeding is a rare cause of acute lower gastrointestinal bleeding, clinicians should consider it during differential diagnosis.

Diagnostic accuracy of endoscopic ultrasound and intraductal ultrasonography for assessment of ampullary tumors: a meta-analysis.

BACKGROUND: Accurate preoperative assessment of ampullary tumors (ATs) is critical for determining the appropriate treatment. The reported diagnostic accuracy of endoscopic ultrasound (EUS) and intraductal ultrasonography (IDUS) for detecting tumor depth (T-staging) and regional lymph node status (N-staging) varies across studies. METHOD: An electronic search of the MEDLINE and Embase databases was conducted to identify studies that assessed the diagnostic accuracy of EUS and IDUS for ATs. Sensitivities and specificities of eligible studies were summarized using either fixed effects or random-effects model. RESULTS: Twenty-one studies were included in the final analysis. The pooled sensitivity and specificity of EUS were 0.89 and 0.87 for T1, 0.76 and 0.91 for T2, 0.81 and 0.94 for T3 and 0.72 and 0.98 for T4, respectively. For IDUS, estimates from five studies were 0.90 and 0.88 for T1, 0.73 and 0.91 for T2 and 0.79 and 0.97 for T3, respectively. For N-staging, 16 studies using EUS were included with sensitivity and specificity of 0.61 and 0.77, respectively. Moreover, estimates of IDUS for N-staging were 0.61 and 0.92, respectively. CONCLUSION: Our results imply that EUS and IDUS have good diagnostic accuracy for T-staging of ATs. However, the accuracy of EUS or IDUS is less satisfactory for N-staging. More well-designed prospective studies are warranted to confirm our findings.

Nomogram for the Prediction of Delayed Colorectal Post-Polypectomy Bleeding.

BACKGROUND: Delayed colorectal post-polypectomy bleeding (PPB) is a fairly common complication after polypectomy. The present study aimed to build a novel nomogram-based model of delayed PPB. METHODS: A cohort of 2494 patients who had undergone colonoscopic polypectomy between January 2016 and April 2020 were consecutively enrolled. The patient demographics, polyp characteristics, laboratory factors, and pathological parameters were collected. The least absolute shrinkage and selection operator (LASSO) regression was applied for selecting potential variables. Multivariate logistic regression was used to develop the nomogram. A bootstrapping method was employed for internal validation. The performance of the nomogram was evaluated on the basis of its calibration, discrimination, and clinical usefulness. RESULTS: Of 2494 patients undergoing colonoscopic polypectomy, 40 (1.6%) developed delayed PPB. The LASSO regression identified 6 variables (age, gender, polyp location, polyp morphology, antithrombotic medication use, and modality of polypectomy), and a predictive model was subsequently established. The area under the curve (AUC) of the predictive model and the internal validation were 0.838 (95% CI: 0.775-0.900) and 0.824 (95% CI: 0.759-0.889), respectively. The predictive model provided acceptable calibration, and a decision curve analysis (DCA) showed its clinical utility. CONCLUSION: This predictive model may enable clinicians to predict the risk of delayed PPB and optimize preoperative decision-making, for effective treatment.

Potent Bispecific Neutralizing Antibody Targeting Glycoprotein B and the gH/gL/pUL128/130/131 Complex of Human Cytomegalovirus.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause developmental disorders following congenital infection and life-threatening complications among transplant patients. Potent neutralizing monoclonal antibodies (MAbs) are promising drug candidates against HCMV infection. HCMV can infect a broad range of cell types. Therefore, single neutralizing antibodies targeting one HCMV glycoprotein often lack either potency or broad cell-type coverage. We previously characterized two human-derived HCMV neutralizing MAbs. One was the broadly neutralizing MAb 3-25, which targets the antigenic domain 2 of glycoprotein B (gB). The other was the highly potent MAb 2-18, which specifically recognizes the gH/gL/pUL128/130/131 complex (pentamer). To combine the strengths of gB- and pentamer-targeting MAbs, we developed an IgG-single-chain variable fragment (scFv) bispecific antibody by fusing the 2-18 scFv to the heavy-chain C terminus of MAb 3-25. The resulting bispecific antibody showed high-affinity binding to both gB and pentamer. Functionally, the bispecific antibody demonstrated a combined neutralization breadth and potency of the parental MAbs in multiple cell lines and inhibited postinfection viral spreading. Furthermore, the bispecific antibody was easily produced in CHO cells at a yield above 1 g/liter and showed a single-dose pharmacokinetic profile comparable to that of parental MAb 3-25 in rhesus macaques. Importantly, the bispecific antibody retained broadly and potent neutralizing activity after 21 days in circulation. Taken together, our research provides a proof-of-concept study for developing bispecific neutralizing antibody therapies against HCMV infection.

Vegetable, Fruit Consumption and Risk of Biliary Cancer: Evidence from a Meta-Analysis.

BACKGROUND AND OBJECTIVE: This meta-analysis was performed to assess the association between vegetable and fruit (VF) consumption and biliary cancer risk. METHOD: Relevant studies were identified by a search of MEDLINE and Embase databases. The summary relative risks (RRs) with 95% confidence intervals (CIs) for the highest vs. lowest consumption and dose-response analyses were assessed. RESULTS: Fourteen studies were eligible. The summary RRs associated with the risk of biliary cancer for the highest vs. lowest were 0.48 (n = 10; 95% CI: 0.22-0.74; Q = 68.27, Pheterogeneity < 0.001, I2 = 86.8%) for vegetable consumption and 0.47 (n = 13; 95% CI: 0.32-0.61; Q = 32.68, Pheterogeneity = 0.001, I2 = 63.3%) for fruit consumption. Dose-response associations were analyzed for every 100 gram/day increment: for vegetable (n = 8; RR = 0.31, 95%CI: 0.20-0.47; Pnon-linearity = 0.35) and for fruit (n = 8; RR = 0.89, 95%CI: 0.66-1.18; Pnon-linearity = 0.20). There was no publication bias among studies (PBegg = 0.53, PEgger = 0.84 for vegetable; PBegg = 0.95, PEgger = 0.64 for fruit). CONCLUSION: This meta-analysis indicated that VF consumption may significantly reduce the risk of biliary cancer. Further well-designed prospective studies are warranted to confirm our findings.

Recognition of a highly conserved glycoprotein B epitope by a bivalent antibody neutralizing HCMV at a post-attachment step.

Human cytomegalovirus (HCMV) is one of the main causative agents of congenital viral infection in neonates. HCMV infection also causes serious morbidity and mortality among organ transplant patients. Glycoprotein B (gB) is a major target for HCMV neutralizing antibodies, yet the underlying neutralization mechanisms remain largely unknown. Here we report that 3-25, a gB-specific monoclonal antibody previously isolated from a healthy HCMV-positive donor, efficiently neutralized 14 HCMV strains in both ARPE-19 cells and MRC-5 cells. The core epitope of 3-25 was mapped to a highly conserved linear epitope on antigenic domain 2 (AD-2) of gB. A 1.8 Å crystal structure of 3-25 Fab in complex with the peptide epitope revealed the molecular determinants of 3-25 binding to gB at atomic resolution. Negative-staining electron microscopy (EM) 3D reconstruction of 3-25 Fab in complex with de-glycosylated postfusion gB showed that 3-25 Fab fully occupied the gB trimer at the N-terminus with flexible binding angles. Functionally, 3-25 efficiently inhibited HCMV infection at a post-attachment step by interfering with viral membrane fusion, and restricted post-infection viral spreading in ARPE-19 cells. Interestingly, bivalency was required for HCMV neutralization by AD-2 specific antibody 3-25 but not the AD-4 specific antibody LJP538. In contrast, bivalency was not required for HCMV binding by both antibodies. Taken together, our results reveal the structural basis of gB recognition by 3-25 and demonstrate that inhibition of viral membrane fusion and a requirement of bivalency may be common for gB AD-2 specific neutralizing antibody.

Virome assembly and annotation in brain tissue based on next-generation sequencing.

The glioblastoma multiforme (GBM) is one of the deadliest tumors. It has been speculated that virus plays a role in GBM but the evidences are controversy. Published researches are mainly limited to studies on the presence of human cytomegalovirus (HCMV) in GBM. No comprehensive assessment of the brain virome, the collection of viral material in the brain, based on recently sequenced data has been performed. Here, we characterized the virome from 111 GBM samples and 57 normal brain samples from eight projects in the SRA database by a tested and comprehensive assembly approach. The annotation of the assembled contigs showed that most viral sequences in the brain belong to the viral family Retroviridae. In some GBM samples, we also detected full genome sequence of a novel picornavirus recently discovered in invertebrates. Unlike previous reports, our study did not detect herpes virus such as HCMV in GBM from the data we used. However, some contigs that cannot be annotated with any known genes exhibited antibody epitopes in their sequences. These findings provide several avenues for potential cancer therapy: the newly discovered picornavirus could be a starting point to engineer novel oncolytic virus; and the exhibited antibody epitopes could be a source to explore potential drug targets for immune cancer therapy. By characterizing the virosphere in GBM and normal brain at a global level, the results from this study strengthen the link between GBM and viral infection which warrants the further investigation.

Identification of adipocyte plasma membrane-associated protein as a novel modulator of human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause disability in newborns and serious clinical diseases in immunocompromised patients. HCMV has a large genome with enormous coding potential; its viral particles are equipped with complicated glycoprotein complexes and can infect a wide range of human cells. Although multiple host cellular receptors interacting with viral glycoproteins have been reported, the mechanism of HCMV infection remains a mystery. Here we report identification of adipocyte plasma membrane-associated protein (APMAP) as a novel modulator active in the early stage of HCMV infection. APMAP is necessary for HCMV infection in both epithelial cells and fibroblasts; knockdown of APMAP expression significantly reduced HCMV infection of these cells. Interestingly, ectopic expression of human APMAP in cells refractory to HCMV infection, such as canine MDCK and murine NIH/3T3 cells, promoted HCMV infection. Furthermore, reduction in viral immediate early (IE) gene transcription at 6 h post infection and delayed nucleus translocation of tegument delivered pp65 at 4 h post infection were detected in APMAP-deficient cells but not in the wildtype cells. These results suggest that APMAP plays a role in the early stage of HCMV infection. Results from biochemical studies of APMAP and HCMV proteins suggest that APMAP could participate in HCMV infection through interaction with gH/gL containing glycoprotein complexes at low pH and mediate nucleus translocation of tegument pp65. Taken together, our results suggest that APMAP functions as a modulator promoting HCMV infection in multiple cell types and is an important player in the complex HCMV infection mechanism.

Setting-Specific and Symptom-Specific Association between Secondhand Smoke Exposure and Depressive Symptoms.

Few studies have focused on the potential relationship between secondhand smoke (SHS) exposure and depressive symptoms. This study aimed to explore the potential association between SHS exposure and depressive symptoms and differentiate this association in setting-specific exposure and symptom-specific outcomes. A cross-sectional study was conducted in Guangdong province of China from September to December 2010 using a multistage sampling method to randomly sample adults aged 18 years and older. SHS exposure was defined as inhalation by non-smokers of the smoke exhaled from smokers for at least 1 day a week in the past 30 days. Depressive symptoms were measured using the nine-item Patient Health Questionnaire. The zero-inflate negative binomial regression models were used to explore the associations between SHS exposure and depressive symptoms. A total of 2771 non-smokers were included in this study, with mean age of 49.6 ± 14.0 years and 70.3% of females. The prevalence of depressive symptoms was significantly higher in participants with SHS exposure than in those without exposure (incidence rate ratio (IRR) = 1.32, 95% confidence interval (CI) 1.16⁻1.51), and there were similar positive associations for SHS exposure in medical facilities (IRR = 1.37, 95% CI 1.17⁻1.61) and in schools (IRR = 1.46, 95% CI 1.20⁻1.77). Notably, there was a monotonically increasing dose-response relationship between frequency of SHS exposure and depressive symptoms. When differentiating this relationship by the dimensions of depressive symptoms, there were similar dose-response relationships for cognitive-affective and somatic symptoms. When differentiating this relationship by sex, only females showed a significant dose-response relationship. Our findings suggest dose-response relationships between SHS exposure and depressive symptoms in sex-specific and symptom-specific manners. Future longitudinal studies are needed to establish the biological mechanisms of the impact of SHS exposure.

Relationship Between Secondhand Smoke Exposure and Depressive Symptoms: A Systematic Review and Dose⁻Response Meta-Analysis.

Previous studies have suggested an association between secondhand smoke (SHS) exposure and risk of depressive symptoms. However, it remains unclear whether there is a dose-response relationship. The effect estimates were pooled using fixed-effect or random-effect models based on homogeneity analysis. The dose-response meta-analysis was performed by linear and non-linear regression. Subgroup analyses were conducted to explore the possible sources of heterogeneity. Twenty-four studies were included in this meta-analysis. SHS exposure was significantly associated with increased odds of depressive symptoms (odds ratio (OR) = 1.32, 95% confidence interval (CI) 1.25-1.39). For SHS exposure expressed as an ordinal variable, the dose-response meta-analysis revealed a monotonically increasing relationship between SHS exposure and depressive symptoms. A similar dose-response relationship was observed for SHS exposure expressed as a continuous variable (OR = 1.57, 95% CI = 1.26-1.87). Our findings suggest that SHS exposure is associated with increasing odds of depressive symptoms in a dose-response manner.

Diagnostic accuracy of fecal calprotectin for screening patients with colorectal cancer: A meta-analysis.

BACKGROUND/AIMS: Fecal calprotectin (FC) is reported to have a broad diagnostic accuracy for colorectal cancer (CRC). Therefore, we explored the diagnostic value of FC for CRC using meta-analytical techniques to substantiate the assertion. MATERIALS AND METHODS: An electronic search of the MEDLINE and Embase databases was conducted to identify studies that assessed the diagnostic accuracy of FC for CRC. The sensitivities and specificities of the eligible studies were summarized using a bivariable random-effects model. RESULTS: In total, 20 studies were included in the final analysis. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of FC for CRC detection were 0.83 (95% confidence interval CI, 0.77-0.88), 0.61 (95% CI, 0.54-0.68), 2.15 (95% CI, 1.82-2.55), and 0.28 (95% CI, 0.21-0.37), respectively. The overall diagnostic odds ratio of FC for CRC was 7.76 (95% CI, 5.41-11.12) with an area under the curve of 0.81 (95% CI, 0.77-0.84), whereas the diagnostic value of FC for colorectal adenoma was relatively inferior (area under the curve, 0.55; 95% CI, 0.51-0.59; diagnostic odds ratio, 1.27; 95% CI, 0.91-1.78). CONCLUSION: The results imply that the FC test, as currently implemented, cannot be recommended for CRC detection.

Dose⁻Response Relationships between Second-Hand Smoke Exposure and Depressive Symptoms among Adolescents in Guangzhou, China.

There has been little focus on the possible association between second-hand smoke (SHS) exposure and depressive symptoms among adolescents. Thus, this study aimed to explore the dose⁻response relationships between SHS exposure and depressive symptoms among adolescents and differentiate these associations in setting-specific exposure and severity-specific outcomes. A cross-sectional study was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Univariable and multivariable logistic regression models were used to explore the potential associations between SHS exposure and depressive symptoms. Among 3575 nonsmoking students, 29.6% were classified as having probable depressive symptoms and 9.6% had severe depressive symptoms. There were monotonically increasing dose⁻response relationships between setting-specific (public places, homes, or indoor/outdoor campuses) SHS exposure and severity-specific (probable or severe) depressive symptoms. When examining these relations by source of exposure, we also observed similar dose⁻response relationships for SHS exposure in campuses from smoking teachers and from smoking classmates. Our findings suggest that regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms among adolescents, and highlight the need for smoke-free environments to protect the health of adolescents.

Frequency-risk relationships between second-hand smoke exposure and respiratory symptoms among adolescents: a cross-sectional study in South China.

OBJECTIVES: Although previous studies have suggested an association between second-hand smoke (SHS) exposure and respiratory symptoms, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency-risk relationships between SHS exposure and respiratory symptoms among adolescents. METHODS: A cross-sectional survey was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. The respiratory symptoms were defined as persistent cough or sputum for three consecutive months during the past 12 months. Self-reported SHS exposure was defined as non-smokers' inhalation of the smoke exhaled from smokers on ≥1 day a week in the past 7 days. The univariable and multivariable logistic regression models were fitted to explore the potential frequency-risk relationships between SHS exposure and respiratory symptoms. RESULTS: Among 3575 students, the overall prevalence of SHS exposure was 69.2%, including 49.5% for SHS in public places, 34.5% in homes, 22.7% in indoor campuses and 29.2% in outdoor campuses. There were significantly increased risks of having respiratory symptoms corresponding to SHS exposure in public places (OR=1.60, 95% CI 1.30 to 1.95), in homes (OR=1.53, 95% CI 1.25 to 1.87), in indoor campuses (OR=1.43, 95% CI 1.14 to 1.79) and in outdoor campuses (OR=1.37, 95% CI 1.10 to 1.69) using no exposure as reference. Notably, we observed monotonic frequency-risk relationships between setting-specific(eg, homes, public places and campuses) SHS exposure and respiratory symptoms. CONCLUSION: Our findings suggest that setting-specific SHS exposure is associated with a significant, dose-dependent increase in risk of respiratory symptoms.

Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid.

Enterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLPΔVP4) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLPΔVP4 was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLPΔVP4 resembles the end product of the viral uncoating process, the 80S empty capsid. VLPΔVP4 is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLPΔVP4 sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well.IMPORTANCE Enterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLPΔVP4, structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLPΔVP4 exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLPΔVP4-induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLPΔVP4 as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses.

Targeting Human-Cytomegalovirus-Infected Cells by Redirecting T Cells Using an Anti-CD3/Anti-Glycoprotein B Bispecific Antibody.

The host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency, though not sufficient to clear the virus. T cells are primarily responsible for the control of viral reactivation. When the host immune system is compromised, as in transplant recipients with immunosuppression, HCMV reactivation and progressive infection can cause serious morbidity and mortality. Adoptive T cell therapy is effective for the control of HCMV infection in transplant recipients. However, it is a highly personalized therapeutic regimen and is difficult to implement in routine clinical practice. In this study, we explored a bispecific-antibody strategy to direct non-HCMV-specific T cells to recognize and exert effector functions against HCMV-infected cells. Using a knobs-into-holes strategy, we constructed a bispecific antibody in which one arm is specific for CD3 and can trigger T cell activation, while the other arm, specific for HCMV glycoprotein B (gB), recognizes and marks HCMV-infected cells based on the expression of viral gB on their surfaces. We showed that this bispecific antibody was able to redirect T cells with specificity for HCMV-infected cells in vitro In the presence of HCMV infection, the engineered antibody was able to activate T cells with no HCMV specificity for cytokine production, proliferation, and the expression of phenotype markers unique to T cell activation. These results suggested the potential of engineered bispecific antibodies, such as the construct described here, as prophylactic or therapeutic agents against HCMV reactivation and infection.