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Principal Investigator: GEORGE M SHAW
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2019
Award: $706,916
Funding agency: National Institute of Allergy and Infectious Diseases
DESCRIPTION (provided by applicant): Recent vaccine studies in nonhuman primates have demonstrated the potential for virus-specific CD8 T cell responses to constrain or eradicate SIV infection. Rhesus CMV (RhCMV) and other persistently and non- persistently replicating vectors have contributed substantially toward these goals, but even the best current immunogens leave approximately 50% of animals unprotected. Realization of the full potential of T cell vaccines will
require the development of novel immunogens that elicit T cell responses of sufficient magnitude, breadth, functionality and tissue distribution that virus replication can be effectively
contained, preferably beginning in the initial hours and days of infection. We propose here a novel vaccine concept that builds upon the successes of recent preclinical vaccine trials. This new strategy is based on our laboratories' very recent and unexpected discovery that a novel set of evolutionarily conserved polypeptides is expressed from the 5' RNA leader sequence - previously termed the 5' "untranslated" region - of HIV-1 and the widely divergent SIV strains mac251/239, E660, SL92b and FTq, and that these peptides are highly immunogenic in vivo. HIV and SIV 5' leader-encoded polypeptides represent a new class of defective ribosomal products (DRiPs), which in other viral infections constitute an important source of peptides for antigen presentation and act as early sentinels of pathogen invasion. Because the 5' RNA leader sequence is part of every spliced and unspliced HIV-1 and SIV RNA message, it is the earliest and most abundant vRNA species in every productively infected cell, making peptides encoded by this region attractive as potential vaccine targets. The current grant proposal will explore this potential by testing the following hypothesis: Novel polypeptides encoded by 5' RNA leader sequences of HIV-1 and SIV are commonly expressed and are immunogenic in natural infection, and when expressed by a RhCMV vectored vaccine, will elicit T cell responses that confer protection in the Indian rhesus macaque - SIVmac239 infection model. Specific aims are: (i) To determine the prevalence, breadth and dynamics of T cell responses to 5' leader peptides in HIV-1 and SIV infection; (ii) To investigate the kinetics of expression and presentation of 5' leader peptides on infected cells and the efficiency of T cell recognition and virus control; (iii) To explore the conservation of 5' leader-encoded T cell epitopes and fitness costs associated with virus escape; and (iv) To evaluate the immunogenicity and protective efficacy of 5' leader-encoded polypeptides as vaccines. The implications of these studies extend beyond HIV/AIDS vaccine research: by demonstrating the expression and immunological recognition of a new class of 5' RNA leader-encoded DRiPs, we have uncovered a new paradigm of lentiviral gene expression relevant to studies of HIV-1 immunopathogenesis, latency and eradication.
Terms: <5' Untranslated Regions><5'UTR><AIDS Virus><ATGN><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Ad vector><Adenoviral Vector><Adenovirus Vector><Alleles><Allelomorphs><Animals><Antibodies><Antigen Presentation><Antigenic Determinants><Antigens><Antiviral Agents><Antiviral Drugs><Antivirals><Applications Grants><Assay><Autologous><Binding><Binding Determinants><Bio-Informatics><Bioassay><Bioinformatics><Biologic Assays><Biological Assay><Blood Plasma><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CMV><CMV vaccine><Cell Body><Cell Line><CellLine><Cells><Chronic><Class I Genes><Complement><Complement Proteins><Containment><Cytomegalovirus><Cytomegalovirus Vaccines><Development><Drug or chemical Tissue Distribution><ELISPOT><Epitopes><Gene Expression><General Viruses><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><Grant><Grant Proposals><HCMV><HHV 5><HHV5><HIV><HIV vaccine><HIV-1><HIV-I><HIV/AIDS Vaccines><HIV1><Hour><Human Herpesvirus 5><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune Surveillance><Immune Targeting><Immune response><Immunochemical Immunologic><Immunologic><Immunologic Surveillance><Immunologic Surveillances><Immunological><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically><Immunologics><In Vitro><Infection><Kinetics><LAV-HTLV-III><Laboratories><Leader Peptide><Leader Signal Peptide><Lymphadenopathy-Associated Virus><MHC Class I><MHC Class I Genes><Macaca mulatta><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Memory><Modeling><Molecular Cloning><Molecular Interaction><Monkeys><Mutation><Mutation Analysis><Non-Polyadenylated RNA><Peptide Leader Sequences><Peptides><Plasma><Plasma Serum><Prevalence><RNA><RNA Gene Products><RNA Splicing><Reading Frames><Reticuloendothelial System, Serum, Plasma><Rhesus><Rhesus Macaque><Rhesus Monkey><Ribo-seq><Ribonucleic Acid><Ribosomes><SIV><Salivary Gland Viruses><Sentinel><Simian Immunodeficiency Viruses><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Source><Splicing><Staining method><Stains><Strains Cell Lines><System><T cell response><T-Cell Activation><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Targeted DNA Modification><Targeted Modification><Testing><Tissue Distribution><Vaccinated><Vaccine Research><Vaccines><Viral><Viral Diseases><Viral load measurement><Virus><Virus Diseases><Virus Replication><Virus-HIV><acute infection><adeno vector><adenovector><anti-viral agents><anti-viral drugs><anti-virals><arm><base><chronic infection><cost><cultured cell line><cytokine><cytomegalovirus group><developmental><enzyme linked immunospot assay><falls><fitness><gene product><genome mutation><host response><human immunodeficiency virus vaccine><immunogen><immunogenic><immunogenicity><immunoresponse><improved><in vivo><mRNA Leader Sequences><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><pathogen><persistent infection><plasmid vaccine><polypeptide><pre-clinical><preclinical><protective efficacy><public health relevance><response><ribosome footprint profiling><ribosome profiling><success><thymus derived lymphocyte><vaccination study><vaccination trial><vaccine efficacy><vaccine study><vaccine trial><vector><vector vaccine><viral infection><viral multiplication><viral replication><virus infection><virus load><virus multiplication><virus-induced disease>