R01AI187065

The role of cryptic influenza virus proteins in replication and pathogenesis - Abstract

Productive infections by RNA viruses require faithful replication of full-length genomes.

Yet many RNA viruses also produce deletion-containing viral genomes (DELVGs), aberrant replication products with large internal deletions.

DELVGs interfere with the replication of wild-type virus and their presence in influenza patients is associated with better clinical outcomes.

The DELVG RNA itself is hypothesized to confer this interfering activity.

DELVGs antagonize replication by out-competing the full-length genome or by triggering innate immune responses.

Here, we show this understanding is incomplete.

We discovered a new inhibitory mechanism mediated by a previously unknown class of viral proteins.

Specifically, we identified hundreds of cryptic viral proteins translated from DELVGs.

These DELVG-encoded proteins (DPRs) include canonical viral proteins with large internal deletions, as well as protein truncations with novel C-termini translated from alternative reading frames.

We show that DPRs are common features of influenza virus infections in culture and in humans.

Preliminary results provide strong support and mechanistic data for DPR-mediated interference of wild-type virus replication.

Yet, as we only recently discovered DPRs, we have limited knowledge on the scope and diversity of DPRs made during infection, the different activities they might possess, and their cumulative impact on disease.

As all RNA viruses make DELVGs, many with the potential to express DPRs, this leaves a large gap in our knowledge across RNA virology.

We address this with three aims.

In Aim 1, we characterize the interference activity of DPRs we have already discovered and establish their mechanism of action.

Aim 2 defines the full repertoire of DPRs from primary influenza virus isolates, and tests almost all possible DPR types by screening a synthetic DPR library.

Aim 3 then investigates the in vivo inhibition by DPRs and establishes their contribution to interference activities that suppress wild-type virus replication and disease.

These self-reinforcing aims will provide a comprehensive view of DPR formation, mode of action, and impact on infection and pathology.

Moreover, the detailed knowledge gained here will be critical in achieving the long-sought goal of developing DELVG-containing viruses as antiviral therapeutics.

University Of Wisconsin System

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Madison, Wisconsin 53715 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)