John Mascola, M.D.
BSL-3 Core Virology Section
Description of Research Program
The Vaccine Research Center core virology laboratory focuses on understanding antibody-mediated protective immune responses against HIV-1 via studies of both the plasma antibody compartment and the B-cell compartment. The goal of these studies is to elucidate mechanisms of virus neutralization and the viral epitopes targeted by neutralizing antibodies, and to translate this information into novel strategies for vaccine design. Our laboratory works closely with the structural virology and structural biology laboratories at the VRC, in order to design and evaluate novel vaccines. New vaccine immunogens are designed based on the latest information from the atomic level structure of the HIV-1 Env glycoprotein complexed to neutralizing antibodies. Our laboratory evaluates the antibody specificities elicited by these vaccines, including the neutralizing activity of sera and the viral epitopes that are vulnerable to neutralizing antibodies. Molecular reporter virus assays allow the study of diverse virus isolate from various regions of the world in order to understand the affect of genetic and antigenic diversity, and viral escape, on neutralizing antibody responses.
We also study the natural immune response to HIV-1 by analyzing the development of serum antibody responses and by analyzing B-cell responses at the level of single antigen-specific B-cells. These methodologies allow a detailed dissection of the humoral immune response to HIV-1 with the goal of understanding how a broadly reactive neutralizing antibody response develops during the course of natural HIV-1 infection, and understanding how the humoral immune system targets vulnerable regions on the HIV-1 Env glycoprotein. Multicolor flow cytometry is used to study the B-cell compartment and to identify antigen-specific B-cells from which monoclonal antibodies can be isolated. The PCR based reconstitution of HIV-1 specific monoclonal antibodies from B-cells allows us to track the evolution of the humoral immune response against HIV-1 and to interrogate mechanisms of viral immune evasion from neutralizing antibodies. The information from these pathogenesis studies, together with studies of the antibody response elicited by vaccine immunogens, is used to inform the design of improved antibody-based vaccines for HIV-1.
Selected Publications
Scheid J, Mouquet H, Feldhan N, Seaman M, Velinzon K, Pereyra F, Walker B, Wardemann H, Ho D, Wyatt RT, Mascola JR, Ravetch JV and Nussenzweig M. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV infected individuals. Nature 2009;458:636-640.
Rose NA, Klein RM, Manion MM, O’Dell S, Phogat A, Chakrabarti B, Hallahan CW, Migueles SA, Wrammert J, Ahmed R, Nason M, Wyatt RT, Mascola JR, Connors M. Frequency and phenotype of human immunodeficiency virus envelope-specific B cells from patients with broadly cross-neutralizing antibodies. J Virol 2009;83:188-199.
Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, Decker JM, Wycuff D, Harris L, Hawkins N, Wood B, Nathe C, Richman D, Tomaras GD, Bibollet-Ruche F, Robinson JE, Morris L, Shaw GM, Montefiori DC, and Mascola JR. Profiling the specificity of neutralizing antibodies in a large panel of HIV-1 plasmas from subtype B and C chronic infections. J Virol 2008; 82:11651 – 11658.
Montefiori DM, Sattentau Q, Flores J, Esparza J and Mascola JR. Antibody-Based HIV-1 Vaccines: Recent developments and future directions. PLoS Medicine 2007;4:e348.
Seaman MS, LeBlanc DF, Grandpre LE, Bartman MT, Montefiori DC, Letvin NL and Mascola JR. Standardized assessment of neutralizing antibody responses elicited in rhesus monkeys immunized with single or multi-clade HIV-1 envelope immunogens. Virology 2007; 367:175-786.
Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, Wu X, Shaw GM, Connors M, Wyatt RT and Mascola JR. Broad HIV-1 neutralization mediated by CD4 binding site antibodies. Nat Med 2007; 13:1032-1034.
Letvin NL, Mascola JR, Gorgone DA, Buzby AP, Xu L, Yang Z-Y, Chakrabarti B, Huang Y, Rao SS, Schmitz JE, Barker BR, Bookstein FL and Nabel GJ. Preserved CD4+ central memory T-cells and survival in vaccinated SIV-challenged monkeys. Science 2006;312:1530-1533.
Mascola JR, Sambor A, Beaudry K, Santra S, Welcher B, Louder MK, Montefiori DC, Nabel GJ and Letvin NL. Neutralizing antibodies elicited by immunization of monkeys with DNA plasmids and recombinant adenoviral vectors expressing HIV-1 proteins. J Virol 2005;79:771-779.
Mascola JR. Defining the protective antibody response for HIV-1. Current Molecular Medicine 2003;3:211-218.
Mascola JR, Louder, MK, Winter C, Prabhakara R, De Rosa, SC, Gabuzda D and Roederer M. HIV-1 neutralization measured by flow cytometric quantitation of single-round infection of primary human T-cells. J Virol 2002;76:4810-21.
Mascola JR, Nabel GJ. Vaccines to prevent human immunodeficiency virus type-1 disease. Current Opinion in Immunology 2001;13:489-495.
Mascola JR, Stiegler G, VanCott TC et. al. Protection of macaques against vaginal transmission of a pathogenic SHIV by passive infusion of neutralizing antibodies. Nat Med 2000;6:207-210.
If you are interested in a Research Fellowship, please send your CV to:
Dr. John Mascola
NIH/Vaccine Research Center
40 Convent Drive
Bldg. 40, Room 4500
Bethesda, MD 20892-3005
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