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Robert W. Doms, M.D., Ph.D.
78
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Professor of Pathology and Laboratory Medicine
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Chair & Pathologist-in-Chief, The Children's Hospital of Philadelphia
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Department: Pathology and Laboratory Medicine
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Contact information
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The Children's Hospital of Philadelphia
37 Department of Pathology and Laboratory Medicine
25 34th & Civic Center Boulevard
4c 5th Floor Floor Main Building - Room 5135
Philadelphia, PA 19104
26
37 Department of Pathology and Laboratory Medicine
25 34th & Civic Center Boulevard
4c 5th Floor Floor Main Building - Room 5135
Philadelphia, PA 19104
2e
Office: 215-590-4446
34 Fax: (215) 590-1021
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34 Fax: (215) 590-1021
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Email:
domsr@email.chop.edu
12
domsr@email.chop.edu
18
Publications
23 a
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2
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23 a
Links
96 Search PubMed for articles
6d Department of Microbiology webpage.
86 Department of Microbiology faculty webpage.
42 Cell and Molecular Biology graduate group faculty webpage.
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1f
96 Search PubMed for articles
6d Department of Microbiology webpage.
86 Department of Microbiology faculty webpage.
42 Cell and Molecular Biology graduate group faculty webpage.
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13
Education:
21 9 B.A. 14 (Biology) c
2d Bucknell University , 1981.
21 9 M.D. c
28 Yale University, 1988.
21 a Ph.D. 19 (Cell Biology) c
45 Yale University Ari Helenius, Thesis Advisor, 1988.
c
3
3
3
3
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Permanent link21 9 B.A. 14 (Biology) c
2d Bucknell University , 1981.
21 9 M.D. c
28 Yale University, 1988.
21 a Ph.D. 19 (Cell Biology) c
45 Yale University Ari Helenius, Thesis Advisor, 1988.
c
2 29
21
1e
1d
24
5e
e - HIV
23 - Emerging viral pathogens
8
62 Key words: HIV, Rift Valley fever virus, Virus-host cell interactions, Andes virus.
8
26 Description of Research
18d 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.
8
431 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.
8
54e 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.
8
301 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.
8
1f Members of the Doms lab
8
b6 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):
8
11 Postdocs:
8
85 Meg Laakso (2/06) Ph.D. Baylor College of Medicine. HIV vaccine development and genetic modification of the viral Env protein
8
d0 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
8
62 Meda Higa (4/07) Ph.D. University of Utah. Bunyaviruses, specifically several Hantaviruses
8
8
11 Students:
8
77 Jessamina Harrison (8/05) B.A. St. Catherine's College. In vivo evolution of resistance to HIV entry inhibitors
8
4d Caroline Agrawal (6/06) B.A. Boston University. HIV fusion inhibition
8
58 Jason Wojcechowskyj (6/08) B.A. University of Wisconsin. Rift Valley Fever virus
8
72 Craig Wilen (3/09) B.S. Washington University. Zinc-finger nuclease mediated disruption of CCR5 and CXCR4.
8
8
14 Technicians:
8
32 Don Pijak (1/97) Res. Spec. D. Lab manager
8
43 Val Hardy (7/02) Res. Tech A. Helps on a number of projects
8
58 Fang-Hua Lee, Ph.D. (2/03) Senior Research Investigator, HIV vaccine development
8
44 Elizabeth Henning (7/09) Res. Spec. A, HIV entry inhibitors.
8
18 Former postdocs:
5d David Cook – Research Assoc. Prof. at the VA Hospital and Univ. Washington, Seattle
36 Debbie Long – Staff Scientist, Wyeth-Lederle
40 Steve Abedon – Associate Professor, University of Ohio
40 Carrie McManus – Staff Scientist, Centocor, Radnor, PA
4a Joe Rucker – Senior Research Scientist, Integral Molecular, Inc.
3e Christine Coughlin - Asst. Prof., University of Denver
29 Benhur Lee – Assoc. Prof., UCLA
45 Frederic Baribaud - Staff Scientist at Incyte, Wilimington DE
4f Stefan Pöhlmann - Asst. Prof., Institute of Virology, Erlangen Germany
3b Ted Pierson - Head, Viral Pathogenesis Section, NIH
4d Bridget Puffer - Senior Research Scientist, Intregral Molecular, Inc.
56 Jackie Reeves – Principal Scientist, Monogram Biosciences, San Francisco, CA
44 Andrea Bertolotti-Ciarlet - Senior Research Biologist, Merck
2e Neela Ray - Scientist in biotechnology
8
18 Former students:
60 Claire Marie Filone - Ph.D., Postdoctoral fellow with Jim Cunningham, Harvard University
54 Lou Altamura – Ph.D., Postdoctoral fellow with Connie Schmaljohn, USAMRIID
5d Sheri Hanna - Ph.D., Postdoctoral fellow with Sara Cherry, University of Pennsylvania
6c Melissa Sanchez - V.M.D./Ph.D., Instructor, University of Pennsylvania School of Veterinary Medicine
59 Carl Davis – M.D./Ph.D., Postdoctoral fellow with Rafi Ahmed, Emory University.
4c Trevor Hoffman – M.D./Ph.D. Student, Clinical Practice, Irvine, CA
58 Aimee Edinger – V.M.D./Ph.D. Asst. Professor, University of California, Irvine
42 Ben Doranz – Founder and CEO of Integral Molecular, Inc.
56 Jason Huse - M.D./Ph.D. Student, Assistant Professor, Memorial Sloan Kettering
3c Adam Crystal - M.D./Ph.D., HemeOnc resident, Harvard
52 Ryan Fortna - M.D./Ph.D., Dermatopathology resident, University of Michigan
26 29
27
Description of Research Expertise
2b Research Interestse - HIV
23 - Emerging viral pathogens
8
62 Key words: HIV, Rift Valley fever virus, Virus-host cell interactions, Andes virus.
8
26 Description of Research
18d 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.
8
431 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.
8
54e 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.
8
301 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.
8
1f Members of the Doms lab
8
b6 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):
8
11 Postdocs:
8
85 Meg Laakso (2/06) Ph.D. Baylor College of Medicine. HIV vaccine development and genetic modification of the viral Env protein
8
d0 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
8
62 Meda Higa (4/07) Ph.D. University of Utah. Bunyaviruses, specifically several Hantaviruses
8
8
11 Students:
8
77 Jessamina Harrison (8/05) B.A. St. Catherine's College. In vivo evolution of resistance to HIV entry inhibitors
8
4d Caroline Agrawal (6/06) B.A. Boston University. HIV fusion inhibition
8
58 Jason Wojcechowskyj (6/08) B.A. University of Wisconsin. Rift Valley Fever virus
8
72 Craig Wilen (3/09) B.S. Washington University. Zinc-finger nuclease mediated disruption of CCR5 and CXCR4.
8
8
14 Technicians:
8
32 Don Pijak (1/97) Res. Spec. D. Lab manager
8
43 Val Hardy (7/02) Res. Tech A. Helps on a number of projects
8
58 Fang-Hua Lee, Ph.D. (2/03) Senior Research Investigator, HIV vaccine development
8
44 Elizabeth Henning (7/09) Res. Spec. A, HIV entry inhibitors.
8
18 Former postdocs:
5d David Cook – Research Assoc. Prof. at the VA Hospital and Univ. Washington, Seattle
36 Debbie Long – Staff Scientist, Wyeth-Lederle
40 Steve Abedon – Associate Professor, University of Ohio
40 Carrie McManus – Staff Scientist, Centocor, Radnor, PA
4a Joe Rucker – Senior Research Scientist, Integral Molecular, Inc.
3e Christine Coughlin - Asst. Prof., University of Denver
29 Benhur Lee – Assoc. Prof., UCLA
45 Frederic Baribaud - Staff Scientist at Incyte, Wilimington DE
4f Stefan Pöhlmann - Asst. Prof., Institute of Virology, Erlangen Germany
3b Ted Pierson - Head, Viral Pathogenesis Section, NIH
4d Bridget Puffer - Senior Research Scientist, Intregral Molecular, Inc.
56 Jackie Reeves – Principal Scientist, Monogram Biosciences, San Francisco, CA
44 Andrea Bertolotti-Ciarlet - Senior Research Biologist, Merck
2e Neela Ray - Scientist in biotechnology
8
18 Former students:
60 Claire Marie Filone - Ph.D., Postdoctoral fellow with Jim Cunningham, Harvard University
54 Lou Altamura – Ph.D., Postdoctoral fellow with Connie Schmaljohn, USAMRIID
5d Sheri Hanna - Ph.D., Postdoctoral fellow with Sara Cherry, University of Pennsylvania
6c Melissa Sanchez - V.M.D./Ph.D., Instructor, University of Pennsylvania School of Veterinary Medicine
59 Carl Davis – M.D./Ph.D., Postdoctoral fellow with Rafi Ahmed, Emory University.
4c Trevor Hoffman – M.D./Ph.D. Student, Clinical Practice, Irvine, CA
58 Aimee Edinger – V.M.D./Ph.D. Asst. Professor, University of California, Irvine
42 Ben Doranz – Founder and CEO of Integral Molecular, Inc.
56 Jason Huse - M.D./Ph.D. Student, Assistant Professor, Memorial Sloan Kettering
3c Adam Crystal - M.D./Ph.D., HemeOnc resident, Harvard
52 Ryan Fortna - M.D./Ph.D., Dermatopathology resident, University of Michigan
26 29
23
de Wojcechowskyj, J.A., J.Y. Lee, S.H. Seeholzer and R.W. Doms. : Quantitative phosphoproteomics of CXCL 12 (SDF-1) signaling. PLos One 6: e24918, 2011.
1a6 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: Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope proteins. J.Virol. Page: epub ahead of print, 2011.
147 Agrawal-Gamse, C., R.J. Luallen, B. Liu, H. Fu, F.H. Lee, Y. Geng and R.W. Doms: Yeast-elicited cross-reactive antibodies to H IV Env glycans efficiently neutralize virions expressing exclusively high-mannoseN-linked glycans. J. Virol. 85: 470-480, 2011.
1ed 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: Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathogens 7: e1002020, 2011.
1e1 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: Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J. Virol. 85: 10669-10681, 2011.
10c Higa, M.M., J. Petersen, J. Hooper and R.W. Doms: Efficient production of Hantaan and Puumala pseudovirions for viral tropism and neutralization studies. Virology Page: epub ahead of print, 2011.
14e Pfaff. J.M., C.B. Wilen, J.E. Harrison, J.F. Demarest, B. Lee, R.W. Doms and J.C. Tilton: HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells. Journal of Virology 84: 6505-6514, Jul 2010.
13b Luallen, R.J., C. Agrawal-Gamse, H. Fu, D.F. Smith, R.W. Doms, Y. Geng: Antibodies against Manalpha1,2-Manalpha1,2-Man oligosaccharide structures recognize envelope glycoproteins from HIV-1 and SIV strains. Glycobiology 20: 280-286, Mar 2010.
179 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: HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. AIDS Research and Human Retroviruses 26: 13-24, Jan 2010.
2c
7
1d
1f
Selected Publications
270 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: 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. PLoS Pathogens 8: e1002686, 2012.de Wojcechowskyj, J.A., J.Y. Lee, S.H. Seeholzer and R.W. Doms. : Quantitative phosphoproteomics of CXCL 12 (SDF-1) signaling. PLos One 6: e24918, 2011.
1a6 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: Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope proteins. J.Virol. Page: epub ahead of print, 2011.
147 Agrawal-Gamse, C., R.J. Luallen, B. Liu, H. Fu, F.H. Lee, Y. Geng and R.W. Doms: Yeast-elicited cross-reactive antibodies to H IV Env glycans efficiently neutralize virions expressing exclusively high-mannoseN-linked glycans. J. Virol. 85: 470-480, 2011.
1ed 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: Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathogens 7: e1002020, 2011.
1e1 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: Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J. Virol. 85: 10669-10681, 2011.
10c Higa, M.M., J. Petersen, J. Hooper and R.W. Doms: Efficient production of Hantaan and Puumala pseudovirions for viral tropism and neutralization studies. Virology Page: epub ahead of print, 2011.
14e Pfaff. J.M., C.B. Wilen, J.E. Harrison, J.F. Demarest, B. Lee, R.W. Doms and J.C. Tilton: HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells. Journal of Virology 84: 6505-6514, Jul 2010.
13b Luallen, R.J., C. Agrawal-Gamse, H. Fu, D.F. Smith, R.W. Doms, Y. Geng: Antibodies against Manalpha1,2-Manalpha1,2-Man oligosaccharide structures recognize envelope glycoproteins from HIV-1 and SIV strains. Glycobiology 20: 280-286, Mar 2010.
179 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: HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. AIDS Research and Human Retroviruses 26: 13-24, Jan 2010.
2c