The need for an effective vaccine against HlV-1 is as urgent as ever. It is currently widely accepted that for a vaccine against HIV to be effective, it should elicit broad and potent anti-HIV neutralizing antibody responses. Anti-HIV neutralizing antibodies (NAbs) target the HIV envelope glycoprotein (Env) on the surface of infectious virions. Despite recent advances in the design of HIV Env-based immunogens, such immunogens have not yet elicited broadly cross-reactive NAbs against primary HIV viruses. The primary reason for this, is that conserved neutralization epitopes, which are present and exposed on such immunogens, are not immunogenic in the context of vaccination. Improving the immunogenicity of such epitopes is crucial for the elicitation of broad anti-HIV neutralizing antibody responses. We currently lack fundamental knowledge on the way B cells recognize such conserved neutralization epitopes on our immunogens and how they subsequently respond to that recognition. In this Project Three, we will investigate how the binding affinity and the duration of the immunogen-BCR interaction, influences the ensuing intracellular events that lead to antibody production. Our plan is to take a 'step back'and examine in detail the interaction between immunogens that express a single HIV neutralization epitope and B cells that express the BCR of that epitope. We will focus our efforts on the epitope recognized by the broadly neutralizing antibody b12. We will determine how the biophysical properties of this interaction define the nature of the ensuing intracellular signaling events that lead to b12-specific B cell antibody responses. These in vitro studies will be complemented by in vivo studies in rhesus macaques (Core B), during which the fate of b12 BCR-expressing B cells will be monitored in the context of immunization and infection. These macaque studies will inform on the evolution of the b12 B cell responses in the contexts of a temporal presentation of immunogen (immunization) and during chronic presentation of the immunogen (SHIV-infection) and on how b12 antibody affinity maturation influences viral-evolution and vice versa.

Public Health Relevance

Our present efforts are highly significant to the eventual development of an effective vaccine against HlV-1, because they aim at understanding the immunological reasons for the lack of immunogenicity of such epitopes on candidate vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI094419-02
Application #
8375319
Study Section
Special Emphasis Panel (ZAI1-BP-A)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$463,646
Indirect Cost
$222,164
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
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McGuire, Andrew T; Glenn, Jolene A; Lippy, Adriana et al. (2014) Diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti-HIV-1 antibodies PG9 and 447-52D. J Virol 88:2645-57
McGuire, Andrew T; Dreyer, Anita M; Carbonetti, Sara et al. (2014) HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. Science 346:1380-3
Finton, Kathryn A K; Friend, Della; Jaffe, James et al. (2014) Ontogeny of recognition specificity and functionality for the broadly neutralizing anti-HIV antibody 4E10. PLoS Pathog 10:e1004403

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