We work at the interface of biochemistry, structural biology, and virology to reveal the mechanistic underpinnings of nucleic-acid binding macromolecular machines.
Our research focuses on herpesviruses, large double-stranded DNA viruses that are prevalent in humans. Nearly everyone will be infected with at least one of the nine human herpesviruses at some point in their lives. Herpesviruses establish life-long infections through cycles of latency and subsequent lytic reactivation that can lead to disease later in life. While many herpesvirus infections are mild or asymptomatic, in
immunocompromised individuals – such as newborns, transplant recipients, and those coinfected with HIV-1 – herpesviruses can have devastating effects. For example, the virus we primarily focus on, Kaposi’s sarcoma-associated herpesvirus (KSHV), can cause cancer. Despite their pervasiveness, we lack a cure for any herpesvirus, and the majority of existing antivirals for treatment target a single viral protein, leading to the development of resistance mutations.
We seek to understand how essential viral processes work and how they can be disrupted. We are currently focusing on viral genome packaging and late gene transcription.
HERPESVIRUS GENOME PACKAGING
Herpesviruses face a unique biophysical challenge: they need to package their long dsDNA genome into a tiny capsid. To do this, they encode one of the most powerful molecular motors known in biology. We want to understand how this motor works and how we can target it with small molecules.
ROLE OF ACCESSORY FACTORS IN PACKAGING
In addition to their powerful molecular motor, herpesviruses encode an accessory protein of unknown function. We recently solved the structure of this protein - ORF68 in KSHV - and seek to identify the mechanistic basis for its essential role in packaging.
LATE GENE TRANSCRIPTION IN GAMMAHERPESVIRUSES
Gammaherpesviruses use a distinctive strategy to produce proteins required at the end of their lytic cycle, like capsid proteins. Late gene transcription depends on six virally encoded factors, termed "viral transcriptional activators", or vTAs. One of these vTAs - ORF24 in KSHV - is unique in that it possesses the ability to directly bind late gene promoters and host RNA polymerase II. The role of the other 5 vTAs remains a mystery that we will continue to tackle.