Major Areas of Research
- Characterize protective immune responses against HIV-1 with a focus on B cells
- Study the natural immune response to HIV-1
- Develop novel strategies for vaccine design
The Humoral Immunology Section (HIMS) focuses on understanding antibody-mediated protective immune responses against HIV-1 using 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 biology laboratories at the VRC 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 to understand the effect 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. Such 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, together with deep sequencing of antibody gene transcripts, 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.
For more information on research conducted by Dr. Mascola, visit the Humoral Immunology Core.
Dr. Mascola serves as Director of the VRC, Chief of the Virology Laboratory, and Chief of the Humoral Immunology Section. He also holds concurrent appointments as adjunct professor of medicine at the Uniformed Services University of the Health Sciences and as a consulting physician in the division of infectious diseases at the Walter Reed National Military Medical Center. Dr. Mascola joined the VRC in October 2000 as deputy director. His research focuses on HIV humoral immune responses and vaccine design. Prior to joining the VRC, Dr. Mascola served as head of HIV prevention research in the division of retrovirology at the Walter Reed Army Institute of Research.
After graduating magna cum laude from Tufts University and earning his medical degree at Georgetown University School of Medicine, Dr. Mascola completed a residency in internal medicine and a fellowship in infectious diseases at the National Naval Medical Center, followed by a fellowship in retroviral diseases at the Walter Reed Army Institute of Research. Dr. Mascola is a Fellow of the American College of Physicians (FACP), a member of the Infectious Diseases Society of America (IDSA), and has been elected to the American Society of Clinical Investigation (ASCI) and the Association of American Physicians (AAP).
Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, Imamichi H, Bailer RT, Chakrabarti B, Sharma SK, Alam SM, Wang T, Yang Y, Zhang B, Migueles SA, Wyatt R, Haynes BF, Kwong PD, Mascola JR, Connors M. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012 Nov 15;491(7424):406-12.
Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O'Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M; NISC Comparative Sequencing Program, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.Science. 2011 Sep 16;333(6049):1593-602.
Letvin NL, Rao SS, Montefiori DC, Seaman MS, Sun Y, Lim SY, Yeh WW, Asmal M, Gelman RS, Shen L, Whitney JB, Seoighe C, Lacerda M, Keating S, Norris PJ, Hudgens MG, Gilbert PB, Buzby AP, Mach LV, Zhang J, Balachandran H, Shaw GM, Schmidt SD, Todd JP, Dodson A, Mascola JR*, Nabel GJ*. Immune and genetic correlates of vaccine protection against mucosal infection by SIV in monkeys. Sci Transl Med. 2011 May 4;3(81):81ra36. (*contributed equally).
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.
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.
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 Sep;13(9):1032-4.