UCSF

Viruses are obligate intracellular parasites and must rely on interactions with host proteins and machinery to produce progeny. Over time, hosts have developed innate immune responses as a first line of defense to control and limit viral infection. This has led to an arms race where viruses find new ways and adaptations to evade host defenses. SARS-CoV-2 encodes a protein called nsp14 which can modify viral mRNA caps to appear more host-like to evade innate immune sensors. Proteomics studies have also found that it binds to several host proteins, including SIRT5, as part of its life cycle but the purpose of this interaction is unknown. HIV and Simian Immunodeficiency Viruses (SIV) encode a protein called Vif to hijack the host E3 ubiquitin ligase complex to target APOBEC3G (A3G), a host antiviral protein, for proteasomal degradation and allow for successful viral replication. This dissertation ties together several different viruses, interactions, and innate immune evasion methods to contribute to our understanding of host-viral interactions. I developed a differential scanning fluorimetry (DSF) assay as a potential screening tool for inhibitors of nsp14 that could be used to combat SARS-CoV-2. I also explored nsp14’s interaction with SIRT5 by contributing purified protein to the research effort. This nsp14/SIRT5 interaction was confirmed to have proviral effects, but the exact mechanism is still unknown. On interactions with HIV and SIV Vif and host A3G, I explored the mechanism behind how a single amino acid mutation in Vif allowed it to antagonize A3G in different species and cross a species barrier. By exploring these different variations of host-viral interactions, we gain a better understanding of viral life cycles and gain knowledge on how to counteract future pandemic viruses.