Herpesviruses are some of the most complex and interesting viruses infecting humans. These viruses establish lifelong dormant infections - many of us are infected with at least one type of herpesvirus, and do not even know it. Unfortunately, these viruses can have detrimental effects on various human populations, yet there is no universal vaccine or cure.
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Our lab studies all herpesvirus subfamilies including Herpes Simplex Virus Type-1 (HSV-1), Human Cytomegalovirus (HCMV), and Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Currently, we combine a variety of biophysical tools, along with chemistry and virology, to understand how viral molecular machines contribute to viral replication. The goal of our work is to provide new insights into how we can more effectively combat these viruses.
CAPSID ASSEMBLY
All herpesviruses require the assembly of a capsid shell to protect the viral genome. This process is essential for successful viral replication and is an attractive therapeutic target. We aim to develop novel biophysical methodologies to dissect the HSV-1 capsid assembly pathway, informing the design of assembly inhibitors and provide new tools for other virologists.
HSV-1 capsid caught in the wild!
Courtesy of Dr. Latifi (Draganova Lab)
CAPSID PACKAGING
Herpesviral capsids overcome amazing biological feats, capable of housing a viral genome under extreme amounts of pressure, while trafficking through the cellular milieu. Despite these forces, the capsid shell stays intact. We seek to understand how they achieve such feats and also understand the limits of these properties.
CAPSID NUCLEAR ESCAPE
The nucleus is the site of herpesviral replication, including capsid assembly and packaging. Here, capsids face yet another obstacle - escaping the nucleus to become mature virions in the cytoplasm. The large size of herpesviral capsids precludes nuclear pore transport and instead, capsids bud out of the nucleus, in a process termed nuclear egress. Budding is mediated by the viral nuclear egress complex (NEC), a virally-encoded budding machine, essential for viral replication. We are currently designing various inhibitors to block NEC activity, both as therapeutic and functional tools.
non-canonical nucleic acids
Image courtesy of Dr. Lowery (Draganova Lab)
Non-canonical nucleic acid structures exist in almost all biological systems, including G-quadruplexes (G4s). Herpesvirus genomes contain sequences predicted to form G4s and can be visualized in infected cells. Interestingly, HSV-1 genomes are highly GC-rich compared to those from the beta (HCMV) and gamma (KSHV) subfamilies yet it is unclear the roles of G4s towards viral replication. Our lab is currently employing G4-stabilizing small molecules to not only map G4 frequency throughout infection, but to also delineate G4 contributions to viral infection.