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Stamatatos: Novel HIV Immunogen Vaccines

OVERVIEW

The Stamatatos-led research consortium takes advantage of the latest discoveries made in immunology, virology, molecular biology and computational-based design methodologies to develop novel strategies to design an anti-HIV vaccine. This team, comprised of investigators with diverse but complementary backgrounds, is working to develop a vaccine that would elicit antibodies capable of preventing infection by multiple HIV-1 strains. To this end, the Stamatatos-led consortium is focusing on eliciting antibodies against regions of the virus that remain structurally conserved among diverse isolates. Two such regions are the focus of intense investigation by this team: 1) the region of the viral envelope that binds to cellular CD4 (the CD4-binding site) and 2) a region located close to the viral membrane, called the membrane proximal external region (MPER), which is targeted by the broadly neutralizing antibody 4E10.

RESEARCH OBJECTIVES

  1. Evaluate the ability of computationally designed immunogens to elicit anti-HIV neutralizing antibodies;
  2. Engineer and evaluate the immunogenic properties of novel trimeric gp140 HIV envelope proteins composed of non-identical gp140 protomers (gp140 heterotrimers);
  3. Define the crystal structure of immunogens, coupled or not to their natural or artificial ligands; and
  4. Isolate and characterize broadly reactive NAbs from SHIV-infected non-human primates that display broad serum neutralizing activity.

PROGRESS

The Stamatatos research consortium performed over 50 immunization studies in animals with novel immunogens and analyzed the elicited antibody responses. The results indicate that computationally-designed immunogens, mixed with appropriate adjuvants, elicit antibodies with the appropriate binding specificities against conserved HIV-1 neutralization epitopes. They were also successful in engineering stable soluble heterotrimeric clade A/B proteins and immunization studies in rabbits show such constructs to be more effective in eliciting neutralizing antibody responses against HIV than previously tested immunogens.

Researchers within the Stamatatos-led consortium obtained and analyzed crystal structures of several of their immunogens and this structural information, combined with their vaccine data, allow them to optimize their vaccine-design efforts.

 

Grant at a Glance

Principal Investigator

Leo Stamatatos, PhD

Grantee Institution

Seattle Biomedical Research Institute, Seattle, USA

Project Title

Discovery of novel HIV neutralizing epitopes and their optimal presentation through computational design of small protein immunogens

Grant Award

$19.4 million over 6 years, awarded August 2006

Collaborating Institutions

  • California Institute of Technology, USA
  • Fred Hutchinson Cancer Research Center, USA
  • Tulane University, USA
  • University of Washington, USA

External Scientific Advisory Board

  • John Mascola, National Institutes of Allergy and Infectious Diseases
  • John Shiver, Merck Research Laboratories
  • Michael Zwick, The Scripps Research Institute

Progress to Date

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