John Mascola, M.D.
Description of Research Program
Recent studies in non-human primates have demonstrated that antibodies directed against gp120 or gp41 epitopes on the HIV-1 envelope glycoprotein can mediate protection. However, current HIV vaccine immunogens do not consistently generate such protective antibody responses. The research program of the BSL3 virology laboratory focuses on understanding antibody-mediated protective immune responses against HIV-1, as well as on novel immunization strategies aimed at eliciting more potent and broadly neutralizing anti-HIV-1 antibodies. The program includes laboratory-based research, small animal immunogenicity studies and non-human primate studies. These studies will be closely coordinated with the structural biology and structural virology laboratories of the VRC in order to better understand how the antigenic structure of the envelope glycoprotein affects the immune response elicited, particularly the neutralizing antibody response. In order to better understand mechanisms by which antibodies block infection of target cells, the BSL3 laboratory has developed quantitative methods to quantify viral neutralization. These methods include precise flow cytometric assays that enumerate infected T-cells, as well as high throughput methods based on single round reporter viruses. These assays will be used to rapidly evaluate novel vaccine immunogens and to map the specificities of antibodies that are elicited. The goal of this program is to understand the neutralization characteristics and epitope specificities of antibodies induced by novel vaccine candidates and to translate this knowledge into improved immunogen design.
Selected Publications
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.
Seaman MS, Beaudry K, Martin KL, Beddall MH, Sambor A, Bailer R, Mascola JR, Nabel GJ, and Letvin NL. Multiclade HIV-1 Envelope Immunogens Elicit Broad Cellular and Humoral Immunity in Rhesus Monkeys. J Virol 2005;79:2956-63.
Grunder C, Li Y, Louder MK, Mascola JR, Yang X, Sodroski J and Wyatt R. Analysis of the neutralizing antibody response elicited in rabbits by repeated inoculation with trimeric HIV-1 envelope glycoprotein. Virology 2005;331:33-46.
Ofek G, Tang M, Sambor A, Katinger H, Mascola JR, Wyatt R and Kwong PD. Structure and mechanistic analysis of the anti-HIV-1 antibody 2F5 in complex with its gp41 epitope. J Virol 2004;78:10724-10737.
Letvin NL, Huang Y, Chakrabarti B, Xu L, Seaman M, Beaudry K, Korioth-Schmitz B, Yu F, Rohne D, Martin K, Kong W-P, Yang Z-Y, Gelman R, Montefiori D, Mascola JR, and Nabel GJ. Heterologous Envelope Immunogens Contribute to AIDS Vaccine Protection in Rhesus Monkeys. J Virol 2004;78:7490-97.
Zhang L, Ribeiro RM, Mascola JR, Lewis MG, Steigler G, Katinger H, Perelson AS, and Davenport MP. Effects of Antibody on Viral Kinetics in SHIV Infection: Implications for vaccination. J Virol 2004;78:5520-22.
Yang Z-Y, Chakrabarti B K, Xu Ling, Welcher B, Kong W-P, Leung K, Panet A, Mascola JR, and Nabel GJ. Selective Modification of Variable Loops Alters Tropism and Enhances Immunogenicity of HIV-1 Envelope. J Virol 2004;78:4029-4036.
Safrit JT, Ruprecht R, Ferrantelli F, Xu W, Kitabwalla M, Van Rompay K, Marthas M, Haigwood N, Mascola JR, Luzuriaga K, Jones SA, Mathieson BJ, Newell ML; Ghent IAS Working Group on HIV in Women Children. Immunoprophylaxis to Prevent Mother-to-Child Transmission of HIV-1. J Acquir Immune Defic Syndr. 2004 Feb 1;35(2):169-177.
Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, Klomp LW, Wijmenga C, Duckett CS, Nabel GJ. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature. 2003 Dec 18;426(6968):853-7.
Brodine SK, Starkey MJ, Shaffer RA, Ito SI, Tasker SA, Barile AJ, Tamminga CL, Stephan KT, Aronson NE, Fraser SL, Wallace MR, Wegner SA, Mascola JR, McCutchan FE. Diverse HIV-1 subtypes and clinical, laboratory and behavioral factors in a recently infected US military cohort. AIDS. 2003 Nov 21;17(17):2521-2527.
Mascola JR, Lewis MG, VanCott TC, Stiegler G, Katinger H, Seaman M, Beaudry K, Barouch DH, Korioth-Schmitz B, Krivulka G, Sambor A, Welcher B, Douek DC, Montefiori DC, Shiver JW, Poignard P, Burton DR, Letvin NL. Cellular immunity elicited by human immunodeficiency virus type 1/ simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies. J Virol. 2003 Oct;77(19):10348-56.
Mascola JR. Defining the protective antibody response for HIV-1. Curr Mol Med. 2003 May;3(3):209-16.
Mascola JR, Montefiori DC. HIV-1: nature's master of disguise. Nat Med. 2003 Apr;9(4):393-4.
Marovich MA, Mascola JR, Eller MA, Louder MK, Caudrelier PA, El-Habib R, Ratto-Kim S, Cox JH, Currier JR, Levine BL, June CH, Bernstein WB, Robb ML, Schuler-Thurner B, Steinman RM, Birx DL, Schlesinger-Frankel S. Preparation of clinical-grade recombinant canarypox-human immunodeficiency virus vaccine-loaded human dendritic cells. J Infect Dis. 2002 Nov 1;186(9):1242-52. Epub 2002 Oct 07.
Baig J, Levy DB, McKay PF, Schmitz JE, Santra S, Subbramanian RA, Kuroda MJ, Lifton MA, Gorgone DA, Wyatt LS, Moss B, Huang Y, Chakrabarti BK, Xu L, Kong WP, Yang ZY, Mascola JR, Nabel GJ, Carville A, Lackner AA, Veazey RS, Letvin NL. Elicitation of simian immunodeficiency virus-specific cytotoxic T lymphocytes in mucosal compartments of rhesus monkeys by systemic vaccination. J Virol. 2002 Nov;76(22):11484-90.
Brachtel EF, Mascola JR, Wear DJ, Ehrenberg PK, Dayhoff DE, Sanders-Buell E, Michael NL, Frankel SS. Demonstration of de novo HIV type 1 production by detection of multiply spliced and unspliced HIV type 1 RNA in paraffin-embedded tonsils. AIDS Res Hum Retroviruses. 2002 Jul 20;18(11):785-90.
Mascola JR. Passive transfer studies to elucidate the role of antibody-mediated protection against HIV-1. Vaccine. 2002 May 6;20(15):1922-5.
Mascola JR, Louder MK, Winter C, Prabhakara R, De Rosa SC, Douek DC, Hill BJ, Gabuzda D, Roederer M. Human immunodeficiency virus type 1 neutralization measured by flow cytometric quantitation of single-round infection of primary human T cells. J Virol. 2002 May;76(10):4810-21.
Mascola JR, Nabel GJ. Vaccines for the prevention of HIV-1 disease. Curr Opin Immunol. 2001 Aug;13(4):489-95.
Kim JH, Mascola JR, Ratto-Kim S, VanCott TC, Loomis-Price L, Cox JH, Michael NL, Jagodzinski L, Hawkes C, Mayers D, Gilliam BL, Birx DC, Robb ML. Selective increases in HIV-specific neutralizing antibody and partial reconstitution of cellular immune responses during prolonged, successful drug therapy of HIV infection. AIDS Res Hum Retroviruses. 2001 Jul 20;17(11):1021-34.
Barnett SW, Lu S, Srivastava I, Cherpelis S, Gettie A, Blanchard J, Wang S, Mboudjeka I, Leung L, Lian Y, Fong A, Buckner C, Ly A, Hilt S, Ulmer J, Wild CT, Mascola JR, Stamatatos L. The ability of an oligomeric human immunodeficiency virus type 1 (HIV-1) envelope antigen to elicit neutralizing antibodies against primary HIV-1 isolates is improved following partial deletion of the second hypervariable region. J Virol. 2001 Jun;75(12):5526-40.
Salminen MO, Ehrenberg PK, Mascola JR, Dayhoff DE, Merling R, Blake B, Louder M, Hegerich S, Polonis VR, Birx DL, Robb ML, McCutchan FE, Michael NL. Construction and biological characterization of infectious molecular clones of HIV-1 subtypes B and E (CRF01_AE) generated by the polymerase chain reaction. Virology. 2000 Dec 5;278(1):103-10.
Mascola JR, Frankel SS, Broliden K. HIV-1 Entry at the Mucosal Surface: Role of Antibodies in Protection. AIDS 2000;14(suppl):S167-174.
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
Wu SJ, Grouard-Vogel G, Sun W, Mascola JR, Brachtel E, Putvatana R, Louder M, Figueira L, Marovich M, Blauvelt A, Hayes C and Frankel, S. Human Skin Langerhans Cells are Targets of Dengue Virus Infection. Nat Med 2000;6:816-820.
Ignatius R, Marovich M, Mehlhop E, Villamide L, Mahnke K, Cox W I, Isdell F, Frankel SS, Mascola JR, Steinman RM. Pope M. Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion. J Virol 2000;74: 11329-11338
Mascola JR, Lewis MG, Stiegler G et. al. Protection of macaques against pathogenic SHIV-89.6PD by passive transfer of neutralizing antibodies. J Virol 1999;73:4009-4018.
VanCott TC, Mascola JR, Loomis-Price L et. al., Cross-subtype neutralizing antibodies induced in baboons by a subtype E CCR5-using gp120 Immunogen based on a primary HIV-1 envelope. J Virol 1999;73:4640-4650.
VanCott TC, Kaminski R, Mascola JR et. al. HIV-1 Neutralizing Antibodies in the Genital and Respiratory Tracts of Mice Intranasally Immunized with Oligomeric gp160. J Immun 1998;160:2000.
Gorny, MK, Mascola JR, Israel SR, et. al. A Human antibody specific for the V3 Loop of HIV-1 clade E cross-reacts with other HIV-1 clades. AIDS Res Hum Retroviruses 1998;14:213-221.
Mascola JR. Neutralization of HIV-1 Infection of Human Peripheral Blood Mononuclear Cells (PBMC): Antibody Dilution Method. In: Michael NL and Kim J eds. Methods in HIV Research. Totowa, NJ: Humana Press Inc. 1999:309-319.
Frankel SS, Steinman RM, Michael NL, Ratto-Kim S, Bhardwaj N, Pope M and Mascola JR. Neutralizing monoclonal antibodies block HIV-1 infection of dendritic cells and transmission to T-cells. J Virol 1998;72:9788-94.
Michael NL, Chang G, Louie LG, Mascola JR, Dondero D, Birx DL, and Sheppard HW. Role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med 1997;3:338-340.
Mascola JR, Louder MK, VanCott TC et al. Potent and synergistic neutralization of HIV-1 primary isolates by hyperimmune anti-HIV immunoglobulin (HIVIG) combined with monoclonal antibodies 2F5 and 2G12. J Virol 1997;71:7198-7206.
Pope M, Frankel SS, Mascola JR, Trkola A, Isdell F, Birx DL, Burke DS, Ho DD, Moore JP. HIV-1 strains from subtypes B and E replicate in cutaneous dendritic cell-T -cell mixtures without displaying subtype-specific tropism. J Virol 1997;71:8001-8007.
Mascola JR, Snyder SS, Weislow OS et al. Vaccination with envelope glycoprotein products induces neutralizing antibodies to laboratory-adapted but not primary isolates of HIV-1. J Infect Dis 1996;173:340-8
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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