Department of Microbiology and Immunobiology
Harvard Medical School
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Research

Our laboratory studies the mechanisms by which herpes simplex virus (HSV) undergoes a productive infection in epithelial cells , expressing over 80 viral genes, versus a latent infection in neurons, where only one transcriptional unit is expressed efficiently. We are also studying the mechanisms of the host immune response to viral infection and the use of mutant strains of HSV as a herpes vaccine and as a vaccine vector.

Productive Infection

The HSV ICP4 protein is required for all early and late viral transcription while the ICP27 protein is required for some E gene expression and all late gene expression. We have found that ICP27 and a viral DNA replication protein, ICP8, associate with the host RNA polymerase II, likely to stimulate late viral transcription. We are investigating the mechanism of the interactions of these viral proteins with polII and the functional significance of their interaction with pol II and other cellular and viral proteins.

Repression of Viral Gene Expression during Infection of Neurons

A unique feature of HSV biology is the persistence of the viral DNA in sensory neurons in a relatively quiescent form. We have shown that the latency-associated transcript represses lytic gene expression in neurons and promotes latent infection, and we are studying the mechanism(s) of this repression.

Replication-defective mutant viruses as a new form of viral vaccine

We have genetically engineered HSV strains that are mutated in essential genes for viral replication. Infection of animals with these mutant viruses induces immunity and protection against virus challenge. We have constructed a double deletion mutant virus that is being developed as a genital herpes vaccine. We have also used HSV recombinants as a vector for simian immunodeficiency virus (SIV) protein expression in immunization studies with Ron Desrosiers' lab. In the first group of immunized animals, 3 of 7 were protected against SIV challenge. Improved recombinants expressing SIV and HIV proteins are being constructed and tested. A unique feature of these vaccine vectors is a durable immune response in which there is antibody maturation over long periods of time after immunization. These results suggest that the replication-defective virus or viral antigens persist in the immunized animal. Future studies will attempt to distinguish between these potential explanations for these observations.