# Role of a novel human-virus chimeric protein generated by upstream translation and genetic overprinting

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $253,625

## Abstract

SUMMARY
The capacity of a pathogen to overcome host barriers and establish infection is based on the
expression of pathogen-derived proteins. To understand how a pathogen antagonizes the host
and establishes infection, we need to have a clear understanding of what proteins a pathogen
encodes, how they function, and in what manner they contribute to virulence. The current
dogma about many life-threatening pathogens is that they encode just a handful of proteins
because of their limited genome. RNA viruses, like Influenza A virus (IAV), are a prime example
of this paradigm. Based on this, our understanding of virus life cycles, pathogenesis, and
therapeutic or prophylactic methods of disease containment are limited to a small set of known
proteins encoded by the viral genome.
We hypothesized that, as a result of host-virus genetic interaction, RNA viruses could generate
chimeric host-virus genes that are translated into proteins during infection. In fact, IAV, and
many other highly pathogenic viruses, use short host RNAs to prime viral transcription to
generate viral mRNA. Thus, we further hypothesized that start codons within host primer
sequences could drive the expression of chimeric human-viral coding sequences, a process that
would depend on the translatability of the viral UTR sequences. Our recent publication indicates
the existence of this mechanism, which creates human-virus protein chimeras either as
extensions of canonical viral proteins or novel polypeptides by genetic overprinting. This idea is
supported by evolutionary analysis and functional data in a few preliminary case studies. The
goal of this exploratory R21 application is to characterize in detail the genomic context that
allows the generation of viral-human proteins along with characterizing, in a physiological
manner, the role of a conserved human-virus protein generated by IAV. A combination of
reserve genetic approaches will be used to generate viral mutants and to fully characterize their
virulence at the cellular and organismal level. By investigating the role of unknown pathogen-
derived proteins, this proposal has the potential to establish their importance, elucidate their role
during infection, and provide a proof-of-principle study for future virology- immunology- and
genomic studies aimed at defining host-virus proteins in the multiple virus in which they can be
generated (3 viral families comprising human, other animal and plant viruses).

## Key facts

- **NIH application ID:** 10369132
- **Project number:** 1R21AI159409-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ivan Marazzi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $253,625
- **Award type:** 1
- **Project period:** 2021-11-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369132

## Citation

> US National Institutes of Health, RePORTER application 10369132, Role of a novel human-virus chimeric protein generated by upstream translation and genetic overprinting (1R21AI159409-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10369132. Licensed CC0.

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