UTMB Department of Pathology

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Molecular pathogenesis and immunology of herpes simplex

A characteristic of herpes simplex virus (HSV) is its ability to establish latent infection in neurons of the peripheral nervous system and thereby persist for the life of the host. The significance of latency is that it represents a reversible interruption of virus replication, and reactivation of replication periodically leads to recurrent episodes of disease. The role of immune cells in the control of neuronal infection has been a focus of my research.

Findings of my laboratory include: The discovery that genes linked to the major histocompatibility complex influence the severity of infection in the peripheral nervous system led to the following observations. First, CD8+ cells, which are generally thought of as cytotoxic (killer) cells, mediate clearance of HSV from the peripheral nervous system without killing neurons. In order to interact with CD8+ lymphocytes, target cells must express class I histocompatibility complex molecules on their surfaces. Conventional wisdom stated that neurons are incapable of such expression. This view was shown to be erroneous. Most recently, the genetic basis for innate resistance to infection with two herpesviruses was mapped to the natural killer cell complex. Two mammalian genes, Cmv1 and Rhs1, have been identified that are responsible for resistance to murine cytomegalovirus and herpes simplex respectively.

Past studies also showed that the molecular pathways leading to latent and productive infection of neurons in vivo with a virulent strain of HSV are divergent at an early stage of the HSV replicative cycle. During latency two patterns of persistence of viral DNA, with respect to the number of copies of the viral genome present in spinal nerve ganglia, were described. Studies on the structure of intermediate DNA molecules formed during the replication of viral DNA during productive infection in cell culture have provided additional insight into the mechanisms that might be involved.

More recently my interests have diversified to include the use of chimeric lymphocytes (T-bodies) for treatment of latent virus infections and cancer. A T-body may be defined as an autologous lymphocyte whose natural target has been redirected to a latent virus or tumor specific antigen by introduction of a chimeric T cell receptor. The most promising approach has been to create chimeric receptors from a single chain antibody variable fragment (scFv) coupled to T cell receptor signaling domains for activation effector functions. A great advantage of this approach is that stimulation of a cell with a scFv-based receptor does not depend on expression of major histocompatibility molecules by the target cells.