This program project brings together a dynamic team of experienced HIV investigators who bring individual and collective strengths to design and test novel vaccines to elicit neutralizing antibodies (NAbs). The overall goal is to design novel vaccines based on env genes from HIV-infected subjects who develop broad NAbs in an accelerated fashion. In Project 1 (L Stamatatos), we will identify multiple HIV-1 infected, ART-naive subjects who developed both autologous and broad cross-neutralizing Abs within the first 2-3 years of infection and characterize the epitope-specificities of these NAbs. With Project 3, we will define changes that accrue to the subjects'cloned quasispecies Envs from initial infection through broadening. We hypothesize that specific diversification of the quasispecies drives maturation of broad cross NAbs in vivo, by presenting new epitopes in escape variants, or by focusing the response on more conserved epitopes. In Project 2 (S Kalams), we will characterize the temporal development and maintenance of functional T-helper (Th) responses that allow B cells to respond to the changes in the Env proteins produced by the patient's quasispecies variants in Project 1. We hypothesize that the initial ability to generate NAbs correlates with a relatively intact CD4+ Th response early in infection, ultimately lost with continued viremia. We will adapt a novel technology to sort Env-specific B cells from these subjects and characterize NAbs that neutralize diverse isolates, to refine our choice of Env immunogens. In Project 3 (N Haigwood), we will work with Project 1 to clone env gp160 variants to define the autologous NAbs and the pathways of env escape;vaccines will be based on these natural longitudinal env variants that arise during broadening. Variants will be used singly and in mixtures to """"""""program"""""""" humoral immunity in vaccinated rabbits and macaques. We hypothesize that the responses in vivo will result in broader NAbs than those elicited by other vaccine strategies. The Program is supported by Core A (Stamatatos) to develop protein immunogens, by Core B (L Picker and M Axthelm) to provide expertise in nonhuman primates and T cell analyses in macaques, and Core C (Haigwood) to support the entire Program with administrative support and biostatistics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-EC-A (J2))
Program Officer
Miller, Nancy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
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
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
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
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

Showing the most recent 10 out of 11 publications