Abstract

The overall goal of our grant proposal is to evaluate the possibility that natural HIV viral env sequences that emerge during the course of HIV infection, can be used as immunogens to elicit broadly-reactive anti-HIV neutralizing antibodies. These env sequences will be derived from HIV infected subjects which during a very short period of time (2-3 years) developed broad and potent anti-HIV cross-neutralizing antibody responses. In Project 1, we will monitor HIV infected subjects to identify those that develop broad cross-neutralizing antibody responses shortly following infection and we will characterize in detail these responses. We will amplify viral env from longitudinal samples from these patients and in conjunction with Project 2 we will examine what role the CD4+ T cell helper responses have in the development and maintenance of broad anti-HIV neutralizing antibody responses. The Envs identified in this Project 1 will be used as immunogens in Project 3 to test the hypothesis that they can elicit broad cross-neutralizing antibody responses in animals.

Public Health Relevance

Our proposed studies will explore a novel concept in the development of an immunization protocol that will lead to the elicitation of broad cross-neutralizing antibodies against HIV. As such, the proposed studies are highly relevant to the development of an effective anti-HIV vaccine.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078064-05
Application #
8495883
Study Section
Special Emphasis Panel (ZAI1-EC-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$611,912
Indirect Cost
$68,503

  Institution

Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Nicholas, Katherine J; Flaherty, David K; Smith, Rita M et al. (2017) Chronic HIV-1 Infection Impairs Superantigen-Induced Activation of Peripheral CD4+CXCR5+PD-1+ Cells, With Relative Preservation of Recall Antigen-Specific Responses. J Acquir Immune Defic Syndr 74:72-80
Nicholas, Katherine J; Greenplate, Allison R; Flaherty, David K et al. (2016) Multiparameter analysis of stimulated human peripheral blood mononuclear cells: A comparison of mass and fluorescence cytometry. Cytometry A 89:271-80
Hessell, Ann J; Malherbe, Delphine C; Pissani, Franco et al. (2016) Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens. J Immunol 196:3064-78
Hessell, Ann J; Haigwood, Nancy L (2015) Animal models in HIV-1 protection and therapy. Curr Opin HIV AIDS 10:170-6
Pissani, Franco; Malherbe, Delphine C; Schuman, Jason T et al. (2014) Improvement of antibody responses by HIV envelope DNA and protein co-immunization. Vaccine 32:507-13
Sather, D Noah; Carbonetti, Sara; Malherbe, Delphine C et al. (2014) Emergence of broadly neutralizing antibodies and viral coevolution in two subjects during the early stages of infection with human immunodeficiency virus type 1. J Virol 88:12968-81
Cohen, Kristen; Altfeld, Marcus; Alter, Galit et al. (2014) Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection. J Virol 88:13310-21
Malherbe, Delphine C; Pissani, Franco; Sather, D Noah et al. (2014) Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J Virol 88:12949-67
Nicholas, Katherine J; Zern, Emily K; Barnett, Louise et al. (2013) B cell responses to HIV antigen are a potent correlate of viremia in HIV-1 infection and improve with PD-1 blockade. PLoS One 8:e84185
Pissani, Franco; Malherbe, Delphine C; Robins, Harlan et al. (2012) Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially. Vaccine 30:5519-26

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