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
Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O'Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010 Aug 13;329(5993):856-61. Epub 2010 Jul 8.
Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. 2010 Aug 13;329(5993):811-7. Epub 2010 Jul 8.
Sundling C, Forsell MN.E., O’Dell S, Feng Y, Rao SS, Lore K, Mascola JR, Wyatt RT, Douagi I, Karlsson Hedestam GB. Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates. J Exp Med. 2010; [In Press]
Sundling C, Forsell MN.E., O’Dell S, Feng Y, Rao SS, Lore K, Mascola JR, Wyatt RT, Douagi I, Karlsson Hedestam GB. Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates. J Exp Med. 2010; [In Press]
Doria-Rose NA, Klein RM, Daniels MG, O'Dell S, Nason M, Lapedes A, Bhattacharya T, Migueles SA, Wyatt RT, Korber BT, Mascola JR, Connors M. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J Virol. 2010 Feb;84(3):1631-6. Epub 2009 Nov 18.
Seaman MS, Janes H, Hawkins N, Grandpre LE, Devoy C, Giri A, Coffey RT, Harris L, Wood B, Daniels MG, Bhattacharya T, Lapedes A, Polonis VR, McCutchan FE, Gilbert PB, Self SG, Korber BT, Montefiori DC, Mascola JR. Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J Virol. 2010 Feb;84(3):1439-52. Epub 2009 Nov 25.
Chen L, Do Kwon Y, Zhou T, Wu X, O'Dell S, Cavacini L, Hessell AJ, Pancera M, Tang M, Xu L, Yang ZY, Zhang MY, Arthos J, Burton DR, Dimitrov DS, Nabel GJ, Posner MR, Sodroski J, Wyatt R, Mascola JR, Kwong PD. Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science. 2009 Nov 20;326(5956):1123-7.
Wu X, Zhou T, O'Dell S, Wyatt RT, Kwong PD, Mascola JR. Mechanism of HIV-1 Resistance to Monoclonal Antibody b12 that Effectively Targets the Site of CD4 Attachment. J Virol. 2009 Nov;83(21):10892-907. Epub 2009 Aug 19.
Dey B, Svehla K, Xu L, Wycuff D, Zhou T, Voss G, Phogat A, Chakrabarti BK, Li Y, Shaw G, Kwong PD, Nabel GJ, Mascola JR, Wyatt RT. Structure-based stabilization of HIV-1 gp120 enhances humoral immune responses to the induced co-receptor binding site. PLoS Pathog. 2009 May;5(5):e1000445. Epub 2009 May 29.
Keele BF, Li H, Learn GH, Hraber P, Giorgi EE, Grayson T, Sun C, Chen Y, Yeh WW, Letvin NL, Mascola JR, Nabel GJ, Haynes BF, Bhattacharya T, Perelson AS, Korber BT, Hahn BH, Shaw GM. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1. J Exp Med. 2009 May 11;206(5):1117-34. Epub 2009 May 4.
Scheid J, Mouquet H, Feldhan N, Seaman M, Velinzon K, Pereyra F, Walker B, Wardemann H, Ho D, Wyatt RT, Mascola JR, Ravetch JV, 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, 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, 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, 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, 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, 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, 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, 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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