Brown Research Interests

Research Projects

1. Disassembly of the HSV-1 tegument. Initiation of infection by herpes family viruses involves a step in which most of the virus tegument becomes detached from the capsid. Detachment takes place in the host cell cytosol near the virus entry site and it is followed by dispersal of tegument proteins and disappearance of the tegument as a distinct entity. We are carrying out studies designed to test the idea that the reducing environment of the host cell cytosol may contribute to tegument detachment and disassembly. The non-ionic detergent Triton X-100 is being used to remove the membrane of purified HSV-1 under control and reducing conditions. The effects on the tegument are then being examined by SDS-polyacrylamide gel electrophoresis and electron microscopy. The results have demonstrated that a reducing environment is required for detachment of tegument protein UL49. The project has also resulted in the isolation of capsids in which UL36 is the only tegument protein present. Investigator: William Newcomb.

2. Role of coatomer in HSV-1 replication. Infection of cells in culture with HSV-1 is found to be accompanied by a large (4X) increase in cellular coatomer, a set of seven proteins involved in vesicle traffic from the golgi apparatus to the endoplasmic reticulum. We are attempting to define the role of coatomer in HSV-1 replication with the idea that it might serve as a therapeutic target to combat HSV-1 infections. Experiments are devoted to testing the idea that coatomer is involved in glycoprotein traffic to the cytoplasmic membrane and determining whether the observed increase in coatomer synthesis is required for HSV-1 replication. Investigator: Jennifer Thompson.

3. Role of DNA repair in herpesvirus pathogenesis. In cells latently infected with a herpesvirus, the viral DNA is present in the cell nucleus, but it is not extensively replicated or transcribed. In this suppressed state the virus DNA is vulnerable to mutagenic events that affect the host cell and have the potential to destroy the virus’ genetic integrity. Despite the potential for genetic damage, however, herpesvirus sequences are well conserved after reactivation from latency. To account for this apparent paradox, we are in the process of testing the idea that host cell-encoded mechanisms of DNA repair are able to control genetic damage to latent herpesvirus genomes. Studies are being focused on homologous recombination-dependent DNA repair (HR). Methods of DNA sequence analysis are being employed to scan herpesvirus genomes for DNA features able to activate HR. A role for HR in virus latency is considered possible if the abundance of one or more of the test features is greater in the virus sequence than in a control, randomized sequence. Investigator: Jay Brown.

Collaborators

  1. Dr. Fred Homa, University of Pittsburgh School of Medicine
  2. Dr. James Conway, University of Pittsburgh School of Medicine
  3. Dr. Lisa Jones, Indiana University Purdue University Indianapolis