An effective HIV vaccine will need to elicit potent humoral and cellular immune responses for true sterilizing immunity. HIV-specific CD4 + T cell responses, particularly proliferative responses, are a potent correlate of control of viremia, but relatively uncommon and of low magnitude in HIV infected individuals. Autologous neutralizing antibodies in HIV infected subjects are typically of low titer, and lack sufficient breadth to neutralize heterologous viruses. Our current HIV vaccine candidates currently under testing in humans are able to elicit CD8+ cellular immune responses, and may well provide partial protection against infection, but are unlikely to generate neutralizing antibodies. This HIVRAD program project will identify viral sequences that elicit broadly neutralizing antibodies in subjects with varying degrees of control of viremia. This particular project (project 2) will take advantage of our access to a large cohort of subjects with early and chronic HIV infection, and which contains several individuals with control of viremia in the absence of anti-retroviral therapy. From years of expertise studying cellular immune responses, and from our preliminary data, we know several of these individuals have intact virus-specific CD4+ T cell responses. Our goalwith this project is to identify interactions between CD4+ T cells and B cells that predict the ability of HIV-infected individuals to generate broadly neutralizing antibodies. We have also designed new technology that allows us to sort B cells specific for HIV envelope, which we will use to isolate B cell clones from subjects with broadly neutralizing antibody activity. The outcome of this project will be a comprehensive picture of helper function required to maintain B cell responses, assays to assess CD4-B cell function in chronically infected and vaccinated individuals, and new antibody reagents that will be used to further characterize HIV neutralizing activity.

Public Health Relevance

Understanding the factors that allow the generation of broadly neutralizing antibodies is critical to vaccine development. In this project we will explore the hypothesis that intact interactions between T cells and B cells is critical to the development and maintenance of broadly neutralizing antibodies in HIV-infected individuals.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Oregon Health and Science University
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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
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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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