UTMB Department of Pathology

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Virus entry and receptor interaction

Enveloped viruses have a protein core, containing the viral genome that is surrounded by a coating of lipid and virus envelope proteins. The role of the envelope protein is to mediate receptor binding and cell entry. This is the first stage of infection and drugs that block this step prevent cell-cell spread of virus and effectively stop infection. The research in my lab is focused on understanding the early events in entry. We employ techniques from structural, molecular and cell biology to study this in detail.

We are studying Murine leukemia virus (a model for HIV) and also Venezuelan equine encephalitis virus (a CDC category 2 agent). These viruses differ fundamentally in the entry trigger mechanism and structures of their envelope proteins. We believe a comparison of each will provide insight into what factors are important for the entry process and give insight into how each uses a different mechanism to achieve the same outcome.

We have made significant recent advances with each of these viruses that will open the door to new and exciting research. Work started by Andrey Kolokoltsov and continued by Drew Deniger has led to the crystallization of a bacterial homolog of the virus receptor for a murine leukemia virus. This represents a significant advance for the field as very few integral membrane proteins and no similar virus receptors have been crystallized before. These crystals diffract and we are hopeful that structural data will come soon. This work builds on previous work by Dr. Davey that yielded the structure of the virus envelope protein (Fass, Davey et al. 1997). The pairing of the envelope to the receptor structures will be unique and provide great insight into how the virus utilizes the receptor to get into the cell.

A second recent advance that we have made is in the design of a rapid virus entry assay (Kolokoltsov and Davey 2004). Here we encapsulate luciferase directly into intact virus particles. When virus enters the cell by membrane fusion the enzyme is freed to react with its substrate to produce light. This is readily detected. Using this assay we are able to demonstrate that actin rearrangement is an important factor for entry. We are currently trying to identify the messengers used to signal this rearrangement.

As this assay is very rapid it opens up the possibility of performing rapid diagnostic assays for virus antibodies in patient serum. Whereas before assays would take many days, the rapid entry assay can determine antibody neutralization titers within 30 minutes. We are presently adapting the assay to important human viral pathogens including HIV and Ebola as well as Venezuelan equine encephalitis virus (Kolokoltsov, Weaver et al. 2004). This is work that is part of the Regional Center of Excellence in Biodefense and Emerging Infections that is funded by the NIH.