Doctor of Philosophy
Microbiology and Immunology
Barr, Stephen D
Although viruses are obligate intracellular parasites, they have their own evolutionary trajectory, their genomes are in a constant battle to overcome the defenses of the host. This thesis investigates the role of the small HERC family of proteins in the battle against two deadly viruses: Human Immunodeficiency Virus -1 (HIV) and Zaire ebolavirus (EBOV). Although their discovery occurred decades ago, little knowledge is available about the small HERC family, their functions, and modes of interactions with other cellular proteins. In the first chapter, the structural evolution of the small HERC family and related functional changes that have occurred over time are explored. We investigate the induction of the small HERC protein by Interferon β and the antiviral activity of HERC5 and HERC6, the most recently emerged members of the small HERC family. We discovered that an ancient form of the HERC5 protein present in the fish species coelacanth has the ability to inhibit the simian immunodeficiency virus (SIV) but not HIV in a similar manner to the human HERC6 protein, whereas the human HERC5 protein inhibits both viruses potently. Focusing more on the interferon induced HERC5 and HERC6 and their contribution to innate immunity, the second chapter focuses on HERC6 and single nucleotide polymorphism which enhances its ability to restrict HIV-1. This SNP confers antiviral activity against HIV-1 in vitro and correlates with disease progression to AIDS in an infected cohort in Uganda. The third chapter illustrates the ability of HERC5 to restrict Ebola virus structural protein VP40 by degrading its RNA, solidifying it as an important weapon in the arsenal of innate immunity. Unfortunately, the glycoprotein of EBOV is able to counteract the restrictive ability of HERC5. The small HERC family and especially HERC5 and HERC6 are emerging as potent antiviral molecules which can combat diverse families of highly pathogenic viruses such as HIV and Ebolavirus. This work advances the knowledge of the small HERC family and more generally the multifaceted ways the innate immune system responds to viral infections in humans.
Summary for Lay Audience
Innate immunity is the body’s ancient and immediate form of defense against harmful organisms. The subtle workings of this protection have evolved over millennia to combat diverse pathogens such as viruses, bacteria, and parasites. Activation of the interferon response is one such defense which produces various proteins to combat these deadly pathogens. Unfortunately, pathogens have developed their own methods of overcoming the immune system, to allow the establishment of infection. In this thesis, I will discuss the various functions of the small HERC family of proteins, a subset of which are activated by the interferon response to fight a variety of viruses. HERC5 and HERC6, two of the most evolutionarily recent members of the small HERC family are interferon induced and have potent antiviral properties. HERC5 has the ability to inhibit the replication of multiple viruses including Human Immunodeficiency virus (HIV-1) and Ebola virus (EBOV) through various mechanisms of actions. First, through its ability to directly modify viral proteins it can inhibit assembly of viral particles. Second, it can inhibit the exit of viral RNA from the nucleus prohibiting the virus from making its structural proteins and forming new progeny. Lastly, to combat EBOV, HERC5 inhibits the production of its structural protein VP40 through the degradation of its RNA. Interestingly, EBOV, via its envelope protein, is able to inhibit the antiviral activities of HERC5. Another antiviral member of the small HERC family, HERC6, is not able to inhibit HIV-1 replication, however, a single amino acid change can restore this potency. The study of the immune system allows for increased understanding of how the body functions to combat viruses and how viruses have evolved elaborate defenses to continue infecting humans. This knowledge would contribute to the development of therapies and treatments to enhance the immune defenses against viruses or conversely, discover novel ways to inhibit viral replication through inhibitions of their functions.
Paparisto, Ermela, "Molecular Characterization of the Antiviral Properties of the Small HERC Family of Proteins" (2023). Electronic Thesis and Dissertation Repository. 9264.
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