Edward A. Berger
Chief, Molecular Structure Section
Description of Research Program
My laboratory has had a long-standing interest in how enveloped viruses enter target cells. We seek to unravel the basic mechanisms of membrane fusion mediated by the interactions of viral envelope glycoproteins with their target cell receptors, and to apply our knowledge to the development of novel strategies to treat and prevent virus infection. We have had a major focus on HIV, but have expanded our studies to diverse enveloped viruses of significance to human health, including herpesviruses and flaviviruses.
We developed specialized expression and reporter gene technologies to study membrane fusion mediated by viral glycoproteins and to screen cDNA libraries for essential cellular receptors. These approaches enabled us to discover the first HIV coreceptor, fusin (subsequently renamed CXCR4), followed by the second major coreceptor, CCR5.
With this information, we have probed the sequential steps by which HIV Env interaction with CD4 and coreceptor triggers membrane fusion and virus entry and the implications for vaccines based on neutralizing antibodies. Our findings led us to devise a novel genetically engineered protein called sCD4-17b that potently neutralizes HIV.
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Top: The 17b mAb is directed against a highly conserved CD4-induced epitope that is involved in binding to CCR5.
Middle: The free 17b mAb cannot access its epitope before CD4-induced gp120 binds to CCR5; hence, no neutralization.
Bottom: sCD4-17b binds to gp120 before the virus encounters the target cell; hence, potent neutralization |
We are currently exploring use of sCD4-17b as a topical microbicide to block sexual transmission of HIV, including genetically modifying Lactobacillus species in the healthy vaginal tract to produce HIV-blocking proteins. We are also developing Env-targeted immunotoxins as an approach to eliminate the reservoirs of HIV-infected cells that persist despite potent antiretroviral therapy.
In our studies of herpesviruses, we collaborated to identify CD46 as the receptor for human herpesvirus-6, and have since defined structure/function relationships in the glycoprotein/receptor interactions.
Most recently, we used functional cDNA expression cloning to identify a novel fusion/entry receptor for KSHV (Kaposi's sarcoma-associated herpesvirus, HHV-8). We are also devising strategies to study entry of flaviviruses such as hepatitis C and West Nile virus, with the goal of identifying receptors, elucidating entry mechanisms, and developing entry-blocking strategies.
Awards
Breakthrough of the Year, Science 1996; AAAS-Newcomb Cleveland Prize; Highly Cited Researchers, ISI; 100 Great Experiments by Great Scientists; Kenneth Fong/Clontech Award; Novartis-Drew Award for Biomedical Science; Damon Runyon-Walter Winchell Foundation Most Prominent Alumni; AMA/NIAID Nathan Davis Award; NIH Outstanding Contributions to Education of Postbaccalaureate Trainees; Norman P Salzman Memorial Mentor Award in Virology, Honorable Mention
Selected Professional Activities
- Institute of Human Virology, Executive Committee, Scientific Advisory Board
- NIAID Technology Evaluation Advisory Committee
- NIH Office of AIDS Research, Coordinating Committee on Etiology & Pathogenesis
- HHMI/NIH Program Advisory Committee
- NIAID Promotion and Tenure Committee
- CONRAD CICCR Global Microbicide Project, Scientific Advisory Group
- NIH Virology Interest Group, Founding Steering Committee Chairperson
- XII International Congress of Virology, Paris, International Scientific Committee, 2002
- Keystone Symposium on HIV Pathogenesis, Lead Organizer, 2001
Research Group Members
Front row (left to right): Yingyun Cai, Postdoctoral Fellow; Deboeeta Chatterjee, Postdoctoral Fellow; Ed Berger, Section Chief; Li Liu, Postdoctodal Fellow. Back row: Vadim Villarroel, Postbaccalaureate Fellow; Laurel Lagenaur, Guest Researcher; Miriam Triyatni, Senior Scientist; Virgilio Bundoc, Senior Research Assistant
Selected Publications
(View list in PubMed.)
Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a 7-transmembrane G protein-coupled receptor. Science 1996; 272: 872-877.
Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy, PM, Berger EA. CC CKR5: a RANTES, MIP-1α, MIP-1ß receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996; 272: 1955-1958.
B Dey, Del Castillo CS, Berger EA. Neutralization of human immunodeficiency virus type 1 by sCD4-17b, a single-chain chimeric protein, based on sequential interaction of gp120 with CD4 and coreceptor. Journal of Virology 2003; 77:2859-2865.
Agrawal L, VanHorn-Ali Z, Berger EA, Alkhatib G. Specific inhibition of HIV-1 coreceptor activity by synthetic peptides corresponding to the predicted extracellular loops of CCR5. Blood 2004;103:1211-1217.
Lusso P, Berger EA, Sironi F, Ripamonti C, Scarlatti, Longhi R, Earl P, Burastero S. Cryptic nature of a conserved, CD4-inducible V3-loop neutralization epitope in the native envelope glycoprotein oligomer of CCR5-restricted, but not CXCR4-using primary HIV-1 strains. Journal of Virology 2005; 79:6957-6968.
Kaleeba JAR, Berger EA. Kaposi's sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT. Science 2006; 311:1921-1924.
NIH Interest Group Memberships
Virology Interest Group, AIDS Interest Group , Viral Hepatitis Interest Group
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