2016 Audrey Gilden Lectureship Anne Gershon Professor of Pediatrics Columbia University

Dr. Anne Gershon received her M.D. in 1964, at the Weill Cornell School of Medicine, where she also underwent residency training in Pediatrics. A postdoctoral fellowship at the Sir William Dunn School of Pathology at Oxford University (1965-1966) followed her clinical training. Subsequently Dr. Gershon joined the Department of Pediatrics at New York University where she remained for 17 years, first as a postdoctoral fellow and eventually rising from Assistant Professor to tenured Professor in 1980. In 1986 she was recruited as Division Director of Pediatric Infectious Diseases and Professor of Pediatrics at Columbia University where she remains today.

She has maintained consistent NIH funding, almost entirely as PI, for the past 40 years. She undertook clinical studies of HIV infection in children in the 1980s and 1090s, but most of her research has focused on basic, translational, and clinical varicella-zoster virus (VZV) infections. Her initial approach was to develop the first sensitive diagnostic methods for this infection, including indications of susceptibility and immunity to varicella and zoster, beginning in the early 1970s, when none of these were available. Success in this area enabled her to study the safety and immunogenicity, as well as protection provided by the newly developed live attenuated varicella vaccine. This vaccine was developed in Japan by Prof. M. Takahashi, who first attenuated VZV; Dr. Gershon joined forces with Dr. Takahashi and his group to further investigate this vaccine. It remains the only licensed human herpesvirus vaccine even today.

Because in the late 1970s children with leukemia were being cured of that disease but dying of varicella, Dr. Gershon organized and led an NIH sponsored national collaborative study of the safety and efficacy of varicella vaccine in leukemic children with the aim of preventing the illness. This unique and extensive study was highly successful and saved many lives; it led to a number of publications showing that the vaccine was safe and effective for these high risk children, and was a major force in the eventual licensure of varicella vaccine (vOka) for healthy children in the U.S. In addition, these studies led to greater understanding of VZV, including the discoveries that viral spread comes primarily from skin lesions and that latency of VZV is related to the infection of the skin, that enervate the cutaneous areas where the rash of varicella occurs as well as by viremia, both mechanisms enabling VZV to reach sensory neurons. Eventually the success of varicella vaccine led to the testing of a vaccine to prevent zoster; the same vaccine was used, but at a dose some 14 times greater than the one to prevent varicella. Zoster vaccine is a therapeutic vaccine that works by stimulating cellular immunity in elderly people with latent VZV infection, who have lost this immune function. Basic studies on VZV, in conjunction with Dr. Michael Gershon in Cell Biology (at Columbia) included identification of the mannose-6-phosphate (MPR), a major receptor for VZV, the mechanism of assembly of VZV in cells, and identification of two different types of spread of VZV, from one cell to another and the other by release of cell free VZV in cells of the superficial epidermis, one of the few cells in the body where MPRs are not present. The release of cell free VZV in the superficial epidermis accounts for spread of virus from one individual to another. It also accounts for development of latent infection in patients with varicella.

More recently, she has investigated latent infection with VZV in humans (autopsy and surgical specimens) and in an in vitro model of latency and reactivation of VZV utilizing enteric neurons of the guinea pig. Enteric ganglia can be dissected from guinea pigs, cultivated in vitro, and infected with cell free VZV with survival for weeks. The neurons in these cultures manifest VZV infection, which have a latency signature of the virus: expression of genes 4, 21, 29, 62, 63, and 66; transcripts and proteins of these regulatory genes are found only in the cell cytoplasm. This signature matches the one we demonstrated in surgical specimens from human gut that contained enteric neurons in which VZV was found to be latent. In vitro, upon introduction of VZV gene 61 into a latently infected guinea pig enteric neuron, the virus reactivates to express all 70 of its genes, and the neuron dies. This unique experimental demonstration of latent infection in intestinal ganglia of guinea pigs was what led to the exploration of whether VZV could be latent in the human gut. We examined human enteric neurons for VZV RNA transcripts to 6 VZV immediate early and early genes that had been associated with latency in human DRG and found RNA from the same 6 genes were present in neurons of human gut tissue that was obtained during medically indicated operative procedures. These data are important because autopsy specimens have been criticized by some groups as non-specific and influenced by time since death and when specimens of DRG were obtained. We also identified vOka infection in the liver of man who had been given a stem cell transplant for lymphoma who died 3 years after inadvertently been given varicella vaccine. We also identified a patient with a gastric ulcer (VZV gE positive) caused by vOka; this 16 year old male recovered; he was initially diagnosed by our finding VZV DNA in his saliva. He had no skin rash. On the basis of these 2 patients with gastrointestinal zoster, we looked for other examples of gut infection using the saliva assay for VZV DNA in patients with typical skin rash of zoster and others with no skin rash but unexplained abdominal pain. In this study 70 % of classic zoster patients were VZV saliva positive and 55% of patients with abdominal pain were saliva positive. Thus testing of saliva for VZV DNA is a useful test for identifying patients with no rash with possible zoster of the gut.

In this lecture, Dr. Gershon will review clinical information regarding varicella and zoster, as well as describe some current theories about latent VZV infection. She will discuss the experience with safety and efficacy of live vaccines against varicella and zoster, and mention the newly developed (not yet licensed) subunit (gE) vaccine against zoster. She will also describe the unique means by which long-term immunity to VZV is maintained, and discuss manifestations of VZV infection of the nervous system of the gut. The ISNV is honored to have Dr. Anne Gershon present the 2016 Audrey Steinman Gilden Lectureship.