Virus Biophysics

Virus Biophysics is a rather new field that seeks to define the physical mechanisms controlling virus development. This knowledge can provide information essential to the rational design of new antiviral strategies with less specificity for a limited number of viruses. Furthermore, biological and physical simplicity relative to other biological systems have made viruses an attractive physical model system to study fundamental prosperities of DNA compaction and translocation as well as protein self-assembly using viral capsids.

Viruses are simple lifeless entities that cannot reproduce on their own and therefore depend on host cells to provide them with the necessary life support mechanisms. Simplified, all viruses consist of a protein shell (capsid) that protects the viral genome (DNA or RNA). To infect, the viral genome must enter the cell, where it hijacks the host cell’s machinery and synthesizes multiple copies of virions. This can lead to cell lysis, which is a lethal event. Alternatively, following viral DNA release into a cell, cell-virus interaction leads to a dormant (so-called latent) state for a virus where its genome remains in the cell without replication which can later reactive and result in cell lysis. Our laboratory investigates physical mechanisms in virus-host interactions that regulate the decision between latency and reactivation. While there are treatments for some lytic viral infections, there is no cure for latent infections which last for the life of the host. Several virus families have spread to pandemic magnitudes among world populations due to their ability to establish latency. Chief among these are the herpesviruses which are currently the focus of our lab.

Figure: Visualization of HSV-1 infection process. Artificially colored electron micrographs of HSV-1 at the cell membrane (a), in transport to the nucleus (b), and bound at a nuclear pore complex (NPC) embedded within the nuclear envelope (c). The dsDNA genome appears as an electron- dense region within the capsid, which is visible in (a) and (b) but absent in (c) due to DNA ejection upon NPC binding. Scale bar, 50 nm.

Developing Antivirals without Drug Resistance

Drug resistance in viruses represents one of the major challenges of healthcare. As part of an effort to provide a treatment that avoids the possibility of drug resistance, we discovered a novel mechanism of action (MOA) and specific compounds to treat all nine human herpesviruses and animal herpesviruses (in the context of veterinary medicine). We recently discovered a high internal DNA pressure of tens of atmospheres in herpesvirus capsids, resulting from tight genome confinement and repulsive DNA-DNA interactions. This pressure is capable of powering ejection of the entire viral genome into a host cell nucleus, leading to infection. The novel MOA targets the pressurized genome state in a viral capsid, “turns off” capsid pressure, and blocks viral genome ejection into a cell nucleus, preventing viral replication. This pivotal finding presents a platform for discovery of a new class of broad-spectrum treatments for herpesviruses and other viral infections with genome-pressure-dependent replication. This is a biophysical approach to treat viral infections independent of the type of virus within the same virus family. This is a vital strategy for treatment of viruses with high mutation rates or other evading strategies that pose a challenge for vaccine development.

Figure: Ultrathin sectioning EM shows that the addition of our antiviral compounds inhibits DNA ejection from HSV-1 C-capsids into a cell nucleus through the NPC. Positive control at 37°C shows complete DNA ejection from C-capsids in the absence of compounds.