Robert W. Doms, M.D., Ph.D.

Chair, Department of Microbiology

Office Address:
University of Pennsylvania School of Medicine
225 Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104

TEL 215-898-0890
LAB 215-898-0891
FAX 215-898-9557
doms@mail.med.upenn.edu

RESEARCH SUMMARY

Research in the Doms lab utilizes a wide array of cell biological, biochemical, genetic, and immunological techniques to study membrane proteins important in HIV/AIDS pathogenesis as well as relatively new research projects on Crimean-Congo Hemorrhagic fever virus, Rift Valley Fever virus and other members of the bunyavirus family.

In order for HIV-1 to enter a cell, the viral Env protein must bind to CD4, the primary virus receptor. However, CD4 binding alone is not sufficient to trigger the conformational changes in Env that lead to membrane fusion and virus entry. For this to occur, the virus must also interact with the appropriate coreceptor. We found that macrophage-tropic virus strains, which are involved in transmission and are the predominant virus type isolated from infected individuals, require the chemokine receptor CCR5 in addition to CD4 for infection to occur. The importance of CCR5 in vivo was shown by our finding that approximately 1% of Caucasian individuals lack CCR5; these individuals are extraordinarily resistant to HIV-1 infection. Over time, T-cell tropic virus strains emerge in some infected individuals; these viruses typically require the chemokine receptor CXCR4 in conjunction with CD4. The discovery of HIV-1 specific coreceptors has important implications for understanding viral tropism pathogenesis, and for the development of novel anti-viral agents.

Current projects involve the use of specific inhibitors of virus entry, many of which are now in clinical trials including the membrane fusion inhibitor T20, which received FDA approval in early 2003 and the CCR5 antagonist maraviroc, which was licensed in 2007. By studying the entry process, we hope to characterize why some virus strains are more sensitive to certain classes of entry inhibitors than other virus strains and to determine if these differences correlate with virus tropism or pathogenesis. This information could also be used to help guide clinical therapy. A great deal of our work in this area involves examining viruses obtained from patients who have received these drugs, as we attempt to identify how HIV acquires resistance to entry inhibitors, and the implications this has for viral tropism.  Finally, now that the structure of the HIV Env protein is better understood and the receptors with which it interacts have been identified, it is now possible to rationally modify the Env protein through genetic means in the hopes of eliciting more effective immunogens. We use both HIV-1, HIV-2 and SIV systems to address these points, comparing closely related virus strains that differ markedly in their pathogenic potential to understand how specific structural alterations can impact virus replication in vivo. Our work in this area is supported by the International AIDS Vaccine Initiative.

Over the past several years, we have initiated projects on Crimean Congo Hemorrhagic fever virus, Sin Nombre virus and Rift Valley fever virus. This work is being done in collaboration with colleagues at USAMRIID at Ft. Detrick, MD as well as the Centers for Disease Control. Cell biological and genetic studies are being done at Penn, while BSL4 work is done at USAMRIID. One of our students is now a postdoctoral fellow at Ft. Detrick. We are generally interested in how these viruses interact with host cells, and in identifying host pathways that are utilized by viruses during their life cycle.  Much of this work is being done in collaboration with Dr. Sara Cherry, who is an expert in applying high throughput RNAi screens to the study of different viruses.

Members of the Doms lab

Current members of the Doms lab, with the month and the year they joined the lab, their previous institution, and a brief description of their projects (updated summer 2008):

Postdocs:

Meg Laakso (2/06) Ph.D. Baylor College of Medicine. HIV vaccine development and genetic modification of the viral Env protein

Chip Tilton (4/06) M.D. Yale University School of Medicine and NIH. In vivo evolution of resistance to CCR5 antagonists by HIV-1 strains

Meda Higa (4/07) Ph.D. University of Utah. Bunyaviruses, specifically several Hantaviruses

Students:

Claire Marie Filone (9/04) B.A. Franklin and Marshall College, Ph.D. student, Rift Valley Fever virus

Jessamina Harrison (8/05) B.A. St. Catherine's College. Resistance of HIV-1 strains to CXCR4 inhibitors

Caroline Agrawal (6/06) B.A. Boston University. HIV vaccine development

Jason Wojcechowskyj (6/08) B.A. University of Wisconsin. Rift Valley Fever virus

Technicians:

Don Pijak (1/97) Res. Spec. D. Lab manager

Val Hardy (7/02) Res. Tech A. Helps on a number of projects

Fang-Hua Lee, Ph.D. (2/03) Senior Research Investigator, HIV vaccine development

Former postdocs:
David Cook – Research Assoc. Prof. at the VA Hospital and Univ. Washington, Seattle
Debbie Long – Staff Scientist, Wyeth-Lederle
Steve Abedon – Associate Professor, The Ohio State University
Carrie McManus – Staff Scientist, Centocor, Radnor, PA
Joe Rucker – Senior Research Scientist, Integral Molecular, Inc.
Christine Coughlin - Asst. Prof., University of Denver
Benhur Lee – Assoc. Prof., UCLA
Frederic Baribaud - Staff Scientist at Incyte, Wilimington DE
Stefan Pöhlmann - Asst. Prof., Institute of Virology, Erlangen Germany
Ted Pierson - Head, Viral Pathogenesis Section, NIH
Bridget Puffer - Senior Research Scientist, Intregral Molecular, Inc.
Jackie Reeves – Principal Scientist, Monogram Biosciences, San Francisco, CA
Andrea Bertolotti-Ciarlet - Senior Research Biologist, Merck
Neela Ray -

Former students:
Lou Altamura – Ph.D., Postdoctoral fellow with Connie Schmaljohn, USAMRIID
Sheri Hanna - Ph.D., Postdoctoral fellow with Sara Cherry, University of Pennsylvania
Melissa Sanchez - V.M.D./Ph.D., Pathology resident, University of Pennsylvania School of Veterinary Medicine
Carl Davis – M.D./Ph.D., Postdoctoral fellow with Rafi Ahmed, Emory University.
Trevor Hoffman – M.D./Ph.D. Pediatric fellow, University of California, Irvine
Aimee Edinger – V.M.D./Ph.D. Asst. Professor, University of California, Irvine
Ben Doranz – Founder and CEO of Integral Molecular, Inc.
Jason Huse - M.D./Ph.D. Clinical fellow, Memorial Sloan Kettering
Adam Crystal - M.D./Ph.D., HemeOnc resident, Harvard
Ryan Fortna - M.D./Ph.D., Dermatopathology resident, University of Michigan