Mechanisms of Ad5-Induced Immune Dysfunction

The failure of an Adenovirus 5 (Ad5)-based human immunodeficiency virus type 1 (HIV-1) vaccine in the STEP trial warranted a detailed evaluation of the immunological properties of Ad5. Previous studies have revealed that immunization with Ad5 induces a partially exhausted T cell response but the mechanism of Ad5-induced immune dysfunction is unknown. Using classical animal models, it has been shown that altering antigen dose, and modulating the PD-1/PD-L1 signaling pathway, or modulating regulatory T cells (Tregs) can influence the quality of memory CD8 T cell. Therefore, we interrogated whether these factors play similar roles in Ad5-induced dysfunction. Here, we show that reducing Ad5 vaccine dose induces highly functional memory CD8 T cell responses, characterized by lower PD-1 expression, higher cytokine co-expression, and an improved recall expansion following a heterologous boost. Interestingly, we show that the dysfunctional recall of Ad5-primed T cells following high-dose immunisation may partly be mediated by a PD-1-dependent CD8 T cell intrinsic phenomenon, as blockade of PD-L1 leads to a substantial improvement in anamnestic T cell expansion. Furthermore, we provide preliminary data suggesting that Treg may not play a crucial role in the development of Ad5-induced dysfunction. Overall, our data contribute to the understanding of the mechanism of Ad5-induced immune dysfunction, and may be relevant for improving vaccination modalities for HIV and other chronic viral infection

Novel Concepts for HIV Vaccine Vector Design

ABSTRACT The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce

Systematic review with meta-analysis: Safety and effectiveness of combining biologics and small molecules in inflammatory bowel disease

BACKGROUND: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. METHODS: We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. RESULTS: Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, CONCLUSIONS: DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain

Nonalcoholic fatty liver disease is a risk factor for thiopurine hepatotoxicity in Crohn\u27s disease

BACKGROUND: Patients with Crohn\u27s disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD. METHODS: In this prospective cohort analysis, CD patients at a single center were recruited 6/2017-5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF \u3e5.5%. Statistical analysis was performed using a Cox-proportional hazards model. RESULTS: Of the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2-7.3, CONCLUSIONS: NAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy

Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization

T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals

Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells

T cell exhaustion occurs during chronic infection and cancers. Programmed cell death protein-1 (PD-1) is a major inhibitory checkpoint receptor involved in T cell exhaustion. Blocking antibodies (Abs) against PD-1 or its ligand, PD-L1, have been shown to reverse T cell exhaustion during chronic infection and cancers, leading to improved control of persistent antigen. However, modeling tumor-specific T cell responses in mouse has been difficult due to the lack of reagents to detect and phenotype tumor-specific immune responses. We developed a novel mouse glioma model expressing a viral epitope derived from lymphocytic choriomeningitis virus (LCMV), which allowed monitoring of tumor-specific CD8 T-cell responses. These CD8 T cells express high levels of PD-1 and are unable to reject tumors, but this can be reversed by anti-PD-1 treatment. These results suggest the efficacy of PD-1 blockade as a treatment for glioblastoma, an aggressive tumor that results in a uniformly lethal outcome. Importantly, this new syngeneic tumor model may also provide further opportunities to characterize anti-tumor T cell exhaustion and develop novel cancer immunotherapies

Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFN gamma signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFN gamma-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFN gamma signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy