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Research Laboratories
BSL-3 Core Virology Laboratory
John Mascola, M.D.
telephone:
301-496-1852
fax: 301-480-0274
email: jmascola@nih.gov
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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