PEOPLE

Robert W. Doms, MD, PhD

Professor of Pathology and Laboratory Medicine and Professor of Microbiology
University of Pennsylvania Perelman School of Medicine
Chair and Pathologist-in-Chief, The Children's Hospital of Philadelphia

Contact InformationThe Children's Hospital of Philadelphia
Department of Pathology and Laboratory Medicine
34th & Civic Center Boulevard
5th Floor Floor Main Building - Room 5135
Philadelphia, PA 19104
Office: 215-590-4446
Fax: (215) 590-1021

Email: domsr@email.chop.edu

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Research Interests
- HIV
- Emerging viral pathogens

Key words: HIV, Rift Valley fever virus, Virus-host cell interactions, Andes virus.

Description of Research
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 Rift Valley Fever virus and other members of the bunyavirus family in which we seek to identify host cell pathways that are used by these viruses to infect cells.

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 used clinically including the membrane fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc. 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 Rift Valley fever virus and several other bunyaviruses that cause disease in humans. 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. 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:

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

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

Craig Wilen (3/09) B.S. Washington University. Zinc-finger nuclease mediated disruption of CCR5 and CXCR4.


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

Elizabeth Henning (7/09) Res. Spec. A, HIV entry inhibitors.

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, 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
Neela Ray - Scientist in biotechnology

Former students:
Claire Marie Filone - Ph.D., Postdoctoral fellow with Jim Cunningham, Harvard University
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., Instructor, 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. Student, Clinical Practice, Irvine, CA
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, Assistant Professor, Memorial Sloan Kettering
Adam Crystal - M.D./Ph.D., HemeOnc resident, Harvard
Ryan Fortna - M.D./Ph.D., Dermatopathology resident, University of Michigan



Graduate Groups

Cell and Molecular Biology

Education

B.A. (Biology), Bucknell University , 1981
Ph.D. (Cell Biology), Yale University Ari Helenius, Thesis Advisor, 1988
M.D. Yale University, 1988

Specialty Certification

American Board of Pathology, 1992

Postgraduate Training

IRTA Fellow, NIH
(Advisor: Bernie Moss), Bethesda, 1988-1989
Postdoctoral Fellow
(Advisor: Ari Helenius), Yale University, 1988-1988
Pathology Resident, NIH
(Advisor: Bernie Moss), Bethesda, 1989-1992

Awards and Honors

Robert P. Vidinghoff Research Scholarship, 1978-1980
Phi Beta Kappa Award, 1981
National Science Foundation Predoctoral Fellowship, 1981-1984
Medical Scientist Training Program, 1983
Gairman Prize for Outstanding Thesis, 1988
Paul Beeson Scholar Award, 1996
American Society for Clinical Investigation, 1997
Stanley N. Cohen Biomedical Research Award, University of Pennsylvania, 1998
Burroughs Wellcome Award for Translational Research, 1998
Anderson Symposium Speaker, University of Virginia, 1998
Elizabeth Glaser Scientist Award, Pediatric AIDS Foundation, 1999
Sidney Grossberg Lectureship, Medical College of Wisconsin, 2001
Pfizer Outstanding Investigator Award, American Society for Investigative Pathology, 2001
Plenary Speaker, 8th National Conference on Retroviruses and Opportunistic Infections, 2001
Plenary Speaker, 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris, France, 2003
Tom Matthews Memorial Lecture: 1st Inhibition of HIV Entry Workshop, 2005
Association of American Physicians, 2006
Fellow, American Society for Microbiology, 2006
Best Basic Science Lecturer, Module 1, 2007
Aaron Wyatt Memorial Lecture, University of British Columbia, 2009
President, AMSMIC (Association of Medical School Microbiology and Immunology Chairs), 2012

Memberships and Professional Organizations

American Association for the Advancement of Science, 2000 - Present
American Society for Microbiology, - Present
Society for Neuroscience, - Present
American Society for Investigative Pathology, - Present
American Society for Clinical Investigation, - Present
American Society for Cell Biology, - Present
American Society for Virology, - Present

Web Links


Selected Publications

Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7

Parrish, N.F., C.B. Wilen, L.B. Banks, S.S. Iyer, J.M. Pfaff, J.F. Salazar-Gonzalez, M.G. Salazar, J.M. Decker, E.H. Parrish, A. Berg, J. Hopper, B. Hora, A. Kumar, T. Mahlokozera, S.Yuan, C. Coleman, M. Vermeulen, C. Ochsenbauer, J.C. Tilton, S.R. Permar, J.C. Kappes, M.R. Betts, M.P. Busch, F. Gao, D. Montefiori, B.F. Haynes, G.M. Shaw, B.H. Hahn and R.W. Doms, PLoS Pathogens 8(): e1002686, 2012, PMID:22693444

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Primary infection by a human immunodeficiency virus with atypical coreceptor tropism

Jiang, C., N.F. Parrish, C.B. Wilen, H. Li, Y. Chen, J.W. Pavlicek, A. Berg, X. Lu, H. Song, J.C. Tilton, J.M. Pfaff, E.A. Henning, J.M. Decker, M.A. Moody, M.S. Drinker, R. Schutte, S. Freel, G.D. Tomaras, R. Nedellec, D.W. Mosier, B.F. Haynes, G.M. Shaw, B.H. Hahn, R.W. Doms and F. Gao, J. Virol. 85(): 10669-10681, 2011, PMID:21835785

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Yeast-elicited cross-reactive antibodies to H IV Env glycans efficiently neutralize virions expressing exclusively high-mannoseN-linked glycans.

Agrawal-Gamse, C., R.J. Luallen, B. Liu, H. Fu, F.H. Lee, Y. Geng and R.W. Doms, J. Virol. 85(): 470-480, 2011, PMID:20962094

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Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases.

Wilen, C.B., J. Wang, J.C. Tilton, J.C. Miller, K.A. Kim, E.J. Rebar, S.A. Sherrill-Mix, S.C. Patro, A.J. Secreto, A.P.O. Jordan, G. Lee, J. Kahn, P.P. Aye, B.A. Bunnell, A.A. Lackner, J.A. Hoxie, G.A. Danet-Desnoyers, F.D. Bushman, J.L. Riley, P.D. Gregory, C.H. June, M.C. Holmes and R.W. Doms, PLoS Pathogens 7(): e1002020, 2011, PMID:21533216

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Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope proteins.

Wilen, C.B., N.F. Parrish, J.M. Pfaff, J.M. Decker, E.A. Henning, H. Haim, J.E. Petersen, J.A. Wojcechowskyj, J. Sodroski, B.F. Haynes, D.C. Montefiori, J.C. Tilton, G.M. Shaw, B.H. Hahn and R.W. Doms, J.Virol., 2011, PMID:21715507

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Efficient production of Hantaan and Puumala pseudovirions for viral tropism and neutralization studies

Higa, M.M., J. Petersen, J. Hooper and R.W. Doms, Virology, 2011

Quantitative phosphoproteomics of CXCL 12 (SDF-1) signaling

Wojcechowskyj, J.A., J.Y. Lee, S.H. Seeholzer and R.W. Doms., PLos One 6(): e24918, 2011, PMID:21949786

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HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells.

Pfaff. J.M., C.B. Wilen, J.E. Harrison, J.F. Demarest, B. Lee, R.W. Doms and J.C. Tilton, Journal of Virology 84(): 6505-6514, 2010, PMID:20410277

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Antibodies against Manalpha1,2-Manalpha1,2-Man oligosaccharide structures recognize envelope glycoproteins from HIV-1 and SIV strains.

Luallen, R.J., C. Agrawal-Gamse, H. Fu, D.F. Smith, R.W. Doms, Y. Geng, Glycobiology 20(): 280-286, 2010, PMID:19920089

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HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.

Tilton, J.C., H. Amrine-Madsen, J.L. Miamidian, K.M. Kitrinos, J. Pfaff, J.F. Demarest, N. Ray, J.L. Jeffrey, C.C. Labranche and R.W. Doms, AIDS Research and Human Retroviruses 26(): 13-24, 2010, PMID:20055594

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