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Richard Wyatt, Ph.D.
Description of Research Program
A daunting task in the
development of a broadly effective HIV-1 vaccine is to elicit humoral immune
responses directed toward conserved, functional elements of the HIV-1 exterior
envelope glycoprotein, gp120. Two functions common to virtually all HIV-1 gp120
glycoproteins are the ability to bind the primary virus receptor, CD4, and to
bind to the more recently defined co-receptors. In a collaborative study, we
have recently solved the crystal structure of gp120, in complex with CD4 and a
neutralizing antibody. This structure uniquely provides us with insight
regarding the means HIV-1 employs to mask these essential functional elements.
HIV-1 is tropic for
CD4-positive cells by virtue of the high affinity interaction between the HIV-1
gp120 glycoprotein, and CD4, which acts as the primary virus receptor. The
gp120 molecule is derived from a gp160 precursor glycoprotein and noncovalently
associates with the transmembrane glycoprotein, gp41, to form trimeric complexes
on the virus or cell surface. The mature HIV-1 gp120 is comprised of five
regions conserved among viral strains (C1-C5) and five regions that exhibit
considerable strain-to-strain variability (V1-V5). Besides CD4, HIV-1 requires
co-factors to achieve entry into target cells. The second receptors used by
HIV-1, primarily CXCR4 and CCR5, belong to a family of seven-membrane spanning,
G-linked proteins which normally function as chemokine receptors.
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A
structure-based schematic representation of the HIV-1 envelope glycoprotein
trimer interacting with the primary receptor, CD4, and the co-receptor, CCR5
present on the target cell. The gp120 exterior envelope glycoprotein is
modeled as a trimer in blue in non-covalent association with the gp41 trimeric
transmembrane glycoprotein in brown. The protruding gp120 third major
variable loop (V3) is shown in cyan.
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During the course of
HIV-1 infection, neutralizing antibodies are elicited against various elements
of gp120. Neutralizing antibodies appear to be an important component of the
host immune response. Most clinical (primary) HIV-1 isolates are relatively
resistant to neutralizing antibodies, suggesting that these viruses are
selected by the presence of neutralizing antibodies in infected humans. In many
HIV-1 infected individuals, two classes of neutralizing antibodies are
elicited: strain-restricted and broadly cross-reactive antibodies. The
strain-restricted antibodies appear early after infection and are generally
directed against linear determinants within the gp120 third variable region.
This class of antibodies has been relatively easy to generate in both primate
and non-primate animal systems but is not broadly protective. A subset of
the broadly neutralizing antibodies recognizes conformationally dependent,
discontinuous epitopes that overlap with the discontinuous CD4 binding site on
gp120 and are termed CD4 binding site antibodies. A second limited subset of
broadly neutralizing antibodies recognizes discontinuous gp120 epitopes,
overlapping with the chemokine receptor binding site, that are better exposed
upon CD4 binding and thus are referred to as CD4-induced antibodies. In naive
individuals, the presence of broadly cross-reactive neutralizing antibodies and
strain-restricted antibodies might help prevent or limit HIV-1 infection
following exposure to the virus.
The broadly neutralizing
antibodies, however, are difficult to elicit in animals using wild-type gp120
glycoproteins as an immunogen. Through several hypotheses based on evolving
structural information of HIV-1 envelope glycoproteins, we will determine if
rational modification of gp120 glycoproteins will influence the exposure and
presentation of conserved, functional structures to the immune system. The
elicitation of antibodies with an expanded breadth of neutralization capacity
may thereby be enhanced. This rational approach to improve gp120 HIV-1 envelope
glycoprotein immunogenicity may have a significant impact on HIV-1 vaccine
design.
Selected Publications
Wyatt R, Kwong P, Desjardins E, Sweet R,
Robinson J, Hendrickson W, Sodroski J. The antigenic structure of the human
immunodeficiency virus gp120 envelope glycoprotein. Nature. 1998;393:705-11.
Kwong P, Wyatt R, Desjardins E, Sweet R,
Robinson J, Sodroski J, Hendrickson W. Structure of an HIV gp120 envelope
glycoprotein in complex with the CD4 and a neutralizing human antibody. Nature.
1998;393:648-59.
Wyatt R, Sodroski J. The HIV-1 envelope
glycoproteins: fusogens, antigens and immunogens. Science.
1998;280:1884-88.
Pancera M, Wyatt R. Selective recognition of
oligomeric HIV-1 primary isolate envelope glycoproteins by potently
neutralizing ligands requires efficient precursor cleavage. Virology. 2005 Feb
5;332(1):145-56.
Pancera M, Lebowitz J, Schon A, Zhu P, Freire E,
Kwong PD, Roux KH, Sodroski J, Wyatt R. Soluble mimetics of human
immunodeficiency virus type 1 viral spikes produced by replacement of the
native trimerization domain with a heterologous trimerization motif:
characterization and ligand binding analysis. J Virol. 2005 Aug;79(15):
9954-69.
Huang CC, Tang M, Zhang MY, Majeed S, Montabana
E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA, Wyatt R, Kwong
PD. Structure of a V3-containing HIV-1 gp120 core. Science. 2005 Nov 11;
310(5750):1025-8 (co-corresponding author).
Li Y, Svehla K, Mathy NL, Voss G, Mascola JR,
Wyatt R. Characterization of Antibody Responses Elicited by Human
Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope
Glycoproteins in Selected Adjuvants. J Virol. 2006 Feb;80(3):1414-26.
Zhou T, Xu L, Dey B, Hessel A, Van Ryk D, Xiang
S-H, Yang X, Zhang M-Y, Zwick M, Arthos J, Burton DR, Dimitrov DS, Sodroski J,
Wyatt R, Nabel GJ, PD Kwong. Structural definition of a conserved
neutralization epitope on HIV-1 gp120. Nature. 2007 Feb 15;445(7129):732-7.
Dey, B, Pancera M, Svehla K, Shu Y, Li Y, Xiang
S-H, Vainshtein J, Sodroski J, Kwong PD, Mascola J, R Wyatt. Characterization
of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120
Glycoproteins Stabilized in the CD4-bound State: Antigenicity, Biophysics and
Immunogenicity. J Virol. 2007 Mar 14
Phogat
S, Svehla K, Tang M, Spadaccini A, Muller J, Mascola J, Berkower
I, Wyatt R, Analysis
of the human immunodeficiency virus type 1 gp41 membrane proximal external
region arrayed on hepatitis B surface antigen particles. Virology. 2007 Dec 21
Karlsson
Hedestam GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT.The challenges of eliciting neutralizing antibodies
to HIV-1 and to influenza virus.Nat Rev Microbiol. 2008 Feb;6(2):143-55.
Forsell
M, Dey B, Mörner A, Svehla K, O'Dell S, Högerkorp C, Voss G, Thorstensson
R, Shaw G, Mascola J, Karlsson Hedestam G, Wyatt RT. B Cell Recognition of the Conserved HIV-1 Co-Receptor
Binding Site Is Altered by Endogenous Primate CD4. PloS Pathogens 2008 Oct
3;4(10)
Li
Y, Svehla K, Louder MK, Wycuff D, Phogat S, Tang M, Migueles SA, Wu X, Phogat
A, Shaw GM, Connors M, Hoxie J, Mascola JR, Wyatt R. Analysis of the Neutralization
Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus
Type-1 Infected Individuals. J Virol 2009; 83 (2):1045-59
N.
A. Doria-Rose, R. M. Klein, M. M. Manion, S. O'Dell, A. Phogat, B. Chakrabarti,
C. W. Hallahan, S. A. Migueles, J. Wrammert, R. Ahmed, M. Nason, R. T. Wyatt, J. R. Mascola, and M. Connors. Frequency and
Phenotype of HIV Envelope-specific B Cells From Patients With Broadly
Cross-Neutralizing Antibodies. J Virol. 2009 Jan;83(1):188-99
Andreas
Morner, Iyadh Douagi, Mattias N E Forsell, Christopher Sundling, Pia Dosenovic,
Sijy O'dell, Barna Dey, Peter D Kwong, Gerald Voss, Rigmor Thorstensson, John
R Mascola, Richard T Wyatt, and
Gunilla B Karlsson Hedestam,
HIV-1 Env-trimer immunization of macaques and impact of priming with
viral vector or stabilized core protein. J Virol. 2008; Jan;83(2):540-51
Scheid
JF, Mouquet H, Feldhahn N, Walker BD, Pereyra F, Cutrell E, Seaman MS, Mascola
JR, Wyatt RT, Wardemann H,
Nussenzweig MC. A method for identification of HIV gp140 binding memory B cells
in human blood. J Immunol Methods. 2008 Dec 25
Scheid JF, Hugo
Mouquet, Niklas Feldhann, Michael S Seaman, Klara Velinzon, John Pietzsch, Rene
Ott, Robert M Anthony, Henry Zebroski, Arlene Hurley, Adhuna Phogat, Bimal Chakrabarti,
Yuxing Li, Mark Connors, Florencia Pereyra, Bruce D Walker, Hedda Wardemann,
David Ho, Richard T Wyatt, John R Mascola, Jeffery V Ravetch and Michel C
Nussenzweig. Broad diversity of neutralizing antibodies isolated from memory B
cells in HIV infected individuals. Nature 2009, in press.
Barna Dey, Krisha
Svehla, Ling Xu, Dianne Wycuff, Tongqing Zhou, Gerald Voss, Adhuna Phogat,
Bimal K. Chakrabarti, Yuxing Li, George Shaw, Peter D.Kwong, Gary Nabel, John
Mascola and Richard Wyatt. Structure-based Modification of HIV-1 gp120 Dramatically
Enhances Conformational Stabilization and Host Immune Responses to a
Discontinuous Epitop. In press, PLoS Pathogens 2009
Pia Dosenovic, Bimal K.
Chakrabarti, Iyadh Douagi, Martina Soldemo, Mattias N. E. Forsell, Adhuna
Phogat, Yuxing Li, Staffan Paulie, James Hoxie, Richard T. Wyatt and Gunilla B. Karlsson Hedestam.
Use of an HIV-1 Env-specific B cell ELISpot assay for quantitative and
qualitative analysis of Env-specific B cell responses following immunization.
JImmunol 2009
At this time, Dr. Wyatt is actively seeking
highly qualified candidates for postdoctoral or predoctoral research fellowship
studies. If you are interested, please email your CV with references to:
Dr. Richard Wyatt, PhD, Professor of Immunology,
Director Viral Immunology,
IAVI Center for Neutralizing Antibodies at TSRI, wyatt@scripps.edu or rwyatt@iavi.org.
Phone: 858 784 7676
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