Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues.

The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

Finding New Communities: A Principle of Neuronal Network Reorganization in Alzheimer's Disease.

Background: Graph-theoretical analyses have been previously used to investigate changes in the functional connectome in patients with Alzheimer's disease (AD). However, these analyses generally assume static organizational principles, thereby neglecting a fundamental reconfiguration of functional connections in the face of neurodegeneration. Methods: Here, we focus on differences in the community structure of the functional connectome in young and old individuals and patients with AD. Patients with AD, moreover, underwent molecular imaging positron emission tomography by using [18F]AV1451 to measure tau burden, a major hallmark of AD. Results: Although the overall organizational principles of the community structure of the human functional connectome were preserved even in advanced healthy aging, they were considerably changed in AD. We discovered that the communities in AD are re-organized, with nodes changing their allegiance to communities, thus resulting in an overall less efficient re-organized community structure. We further discovered that nodes with a tendency to leave the communities displayed a relatively higher tau pathology burden. Discussion: Together, this study suggests that local tau pathology in AD is associated to fundamental changes in basic organizational principles of the human connectome. Our results shed new light on previous findings obtained by using the graph theory in AD and imply a general principle of the brain in response to neurodegeneration.