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 either HIV/AIDS or Alzheimer's Disease pathogenesis. In addition, new research projects on West Nile virus, Crimean-Congo Hemorrhagic fever virus, Rift Valley Fever virus and other emerging infectious diseases are also underway.

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. 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. In addition, 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. Finally, we study virus attachment factors such as DC-SIGN, a lectin like protein expressed at high levels on some types of dendritic cells. DC-SIGN efficiently captures HIV and presents it to adjoining T-cells, resulting in highly efficient virus infection. Other pathogens also utilize DC-SIGN, including Ebola and HCV.

West Nile virus has spread rapidly throughout the United States since first being reported in the New York city area in 1999. While there were approximately 100 cases of West Nile virus encephalitis reported in 2001, there were more than 4000 cases reported in 2002 with more than 250 deaths. We are studying the antigenic structure of WNV and the structure and function of its envelope proteins. We hope to characterize WNV tropism, its mechanism of cell entry, and to identify virus attachment factors and receptors. Our genetic systems can also be applied to other flaviviruses such as Dengue and Yellow fever. Our newest emerging pathogen project concerns bunyaviruses, specifically Crimean Congo Hemorrhagic fever virus and Rift Valley fever virus. This work is being done in collaboration with colleagues at USAMRIID at Ft. Detrick, MD (the “Hot Zone”). Cell biological and genetic studies are being done at Penn, while BSL4 work is done at USAMRIID. One of our students has completed the security clearance necessary for him to work in the BSL4 at Ft. Detrick. Our Rift Valley fever virus work is focused on vaccine development, and is being done in collaboration with Dr. Mark Heise at the University of North Carolina and with Dr. Felicity Burt and colleagues in South Africa.

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 2007):

Postdocs:

Neela Ray (8/04) Ph.D. Princeton University. HIV entry mechanisms, resistance pathways to entry inhibitors

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. Evolution of the humoral immune response to HIV in the face of entry inhibitor therapy; in vivo resistance of HIV to CCR5 inhibitors

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


Students:

Lou Altamura (9/03) B.S. Ursinus College, Ph.D. student, working on Crimean Congo Hemorrhagic fever virus

Claire Marie Filone (9/04) B.A. Franklin and Marshall College, Ph.D. student, working on bunyaviruses

Jessamina Harrison (8/05) B.A. St. Catherine's College. In vivo evolution of resistance to HIV entry inhibitors

Caroline Agrawal (6/06) B.A. Boston University. HIV fusion inhibition

Lauren Davis (6/07) B.A. Oklahoma State University. Crimean Congo Hemorrhagic Fever Virus glycoprotein function


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) HIV vaccine development

Phil Arca (1/04) Res. Spec. A. IAVI HIV vaccine project

Leslie Blackburn Res. Spec. A. HIV entry inhibitors


Former postdocs:
David Cook – Research Asst. Prof. at the VA Hospital and Univ. Washington, Seattle
Nelson Cole - Postdoctoral Fellow, NIH
Debbie Long – Staff Scientist, Wyeth-Lederle
Steve Abedon – Associate Professor, University of Ohio
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

Former students:
Sheri Hanna - Ph.D. Postdoctoral Fellow, 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. Student, Completing medical school, Univ. Pennsylvania
Trevor Hoffman – M.D./Ph.D. Student, 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. Student, Pathology resident, University of Pennsylvania
Vanessa Morais - Visiting Ph.D. student
Adam Crystal - M.D./Ph.D. student, University of Pennsylvania
Ryan Fortna - M.D./Ph.D. student, University of Pennsylvania
Nathalie Schaller - Visiting Ph.D. student