application): Dr. Michael Sherman became keenly interested in science during high school where he admired the process of research as a systematic tool for answering questions of the unknown. At a science school for motivated children that he attended, this interest was nurtured and later propelled him on to complete a research honors thesis project while attending Cornell University. At medical school, he embraced the scientific process as it applied to patient care while obtaining an M.D. and a Ph.D. His basic science orientation led him to pursue clinical oncology, which he felt was the most scientifically rigorous area of medicine. His interest in retrovirology was spawned by his Ph.D. work. He studied HTLV biology under the guidance of Dr. Bernard Poiesz, Director of the Clinical Oncology Center at SUNY Upstate Medical Center, who served as a role model of a clinician-scientist and motivated him to pursue a fellowship at UCSF and specifically at San Francisco General Hospital (SFGH). There at the Positive Health Program (PHP), oncology and HIV-infected patients are seen as one cohort with life-threatening illnesses. The PHP provides exposure to patients with HIV, malignancies, or both. Environment: The association of the SFGH clinical ward with the Gladstone Institute of Virology is close physically and in the approach to science. Dr. Paul Volberding, Director of the PHP, is a clinical oncologist and world-renowned AIDS specialist who works with the mentor, Dr. Warner Greene, to combine clinical and basic science research in HIV biology. The candidate has benefited greatly from an environment where basic science questions are generated from clinical observations. Gladstone matches its world class facilities with outstanding intellectual stimulation. The candidate's personal goals are to become an independent investigator, studying basic science questions in retrovirology and molecular biology. He hopes to continue patient interactions as well. That experience provides new insights and also grounds his basic science research in the practical realities of patient care. Research: His interests in the processes of oncogenesis and HIV-1 infection have led Dr. Sherman to study the basic biology of the HIV accessory viral protein R (Vpr). Vpr, a nucleophilic 96-amino acid protein, facilitates import of the large viral prointegration complex (PIC) across the limiting nuclear pore and induces G2 cell-cycle arrest in T cells, thereby creating a better intracellular milieu for LTR transcription. However, the role of Vpr has been studied in isolated macrophages where weeks of culture and low viral inputs are required. Furthermore, the coding sequence of Vpr is not maintained in long-term cell line and PBMC cultures. Thus, the true role of Vpr may not be truly reflected in the in vitro assays employed thus far. In this application, preliminary evidence is provided that Vpr contains a nuclear export signal and two novel import signals. They propose a systematic strategy to elucidate the role of Vpr shuttling in the context of virion-associated protein and soluble Vpr, using the ex Vito Lymphoid histoculture system that may ultimately reflect a condition closer to the in vivo situation.
| Sherman, Michael P; de Noronha, Carlos M C; Eckstein, Lauren A et al. (2003) Nuclear export of Vpr is required for efficient replication of human immunodeficiency virus type 1 in tissue macrophages. J Virol 77:7582-9 |
| Sherman, Michael P; Greene, Warner C (2002) Slipping through the door: HIV entry into the nucleus. Microbes Infect 4:67-73 |
| de Noronha, C M; Sherman, M P; Lin, H W et al. (2001) Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294:1105-8 |
| Eckstein, D A; Sherman, M P; Penn, M L et al. (2001) HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells. J Exp Med 194:1407-19 |
