Richard Wyatt, Ph.D.
Structural Virology Section
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. |
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, have been 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.
Grundner C, Mirzabekov T, Sodroski J, Wyatt R. Solid-phase proteoliposomes containing human immunodeficiency virus envelope glycoproteins. J Virol. 2002;76:3511-21.
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;[Epub ahead of print].
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
Chief, Structural Virology Section
email: richardwyatt@nih.gov
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