The vast majority of HIV infected individuals develop antibodies to the virus. In most cases the antibodies only target the autologous strain, but some individuals develop neutralizing serologic responses to a broad range of different viral isolates. These responses are of interest because passive transfer of monoclonal antibodies with broad neutralizing activity to humanized mice or monkeys prevents infection. On the basis of these observations it has been proposed that a vaccine that elicits broadly neutralizing antibodies would be protective against HIV. However, little is known about the nature ofthe broadly neutralizing response. Only a small number of patients have been studied to date, and the majority of these patients were selected because their serologic activity was focused on the CD4 binding site ofthe viral envelope spike. The long- term goals of this proposal are to characterize new broadly neutralizing antibodies in terms of their functions in vivo and to understand how HIV-1 develops resistance to these antibodies in vivo. To accomplish these goal we propose three specific aims. First, we will develop an in vivo assay to assess the ability of broadly antibodies to prevent viral entry in mice. HIV neutralization is currently assayed in vitro using TZM-bl cells. The new mouse model will be used to examine the relative efficacy of different monoclonal antibodies and the contribution of innate effector mechanisms to blocking HIV entry in vivo. Second, we will define the basis for development of resistance to broadly neutralizing antibodies in HIV infected humanized mice. We will use the information for structure based rational design approaches to iteratively enhance antibody breadth and potency. The ultimate goal of this part of the proposal is to determine which of the large group of currently available antibodies might be most useful for passive vaccine and immunogen design approaches. Finally, we will evaluate potential immunogens designed using structural and other data in knock-in mice containing human germline antibody precursor genes. Taken together, these experiments should help inform future clinical studies in which neutralizing antibodies might be considered for use in passive therapy or prevention studies and which of their targets would be most useful for immunization strategies.

Public Health Relevance

Although there is still no vaccine for HIV, a small number of infected individuals develop antibodies that can prevent the infection. The proposed research aims to develop an understanding of these antibodies with the long term goal of being able to elicit them de novo as a component of a vaccine to be used in un-infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI100148-01A1
Application #
8517322
Study Section
Special Emphasis Panel (ZAI1-RRS-A (J1))
Project Start
Project End
Budget Start
2013-02-10
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$312,385
Indirect Cost
$57,457
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
West Jr, Anthony P; Scharf, Louise; Scheid, Johannes F et al. (2014) Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156:633-48
Klein, Florian; Nogueira, Lilian; Nishimura, Yoshiaki et al. (2014) Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants. J Exp Med 211:2361-72
Halper-Stromberg, Ariel; Lu, Ching-Lan; Klein, Florian et al. (2014) Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989-99
Bournazos, Stylianos; Klein, Florian; Pietzsch, John et al. (2014) Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158:1243-53
Ahmed, Alysia A; Giddens, John; Pincetic, Andrew et al. (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Mol Biol 426:3166-79
Scharf, Louise; Scheid, Johannes F; Lee, Jeong Hyun et al. (2014) Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7:785-95
Diskin, Ron; Klein, Florian; Horwitz, Joshua A et al. (2013) Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies. J Exp Med 210:1235-49
Shingai, Masashi; Nishimura, Yoshiaki; Klein, Florian et al. (2013) Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503:277-80
Horwitz, Joshua A; Halper-Stromberg, Ariel; Mouquet, Hugo et al. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A 110:16538-43
Chuang, Gwo-Yu; Acharya, Priyamvada; Schmidt, Stephen D et al. (2013) Residue-level prediction of HIV-1 antibody epitopes based on neutralization of diverse viral strains. J Virol 87:10047-58

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