Attempts to induce broadly reactive and potent protective anti-HIV antibodies (Abs) by immunization of humans have been unsuccessful. The optimal vaccine-induced Abs are usually considered to be "neutralizing Abs" that have been defined by studies of several human monoclonal Abs (mAbs) as targeting epitopes in the membrane proximal external region of gp41 and in various regions of gp120 including the CD4 binding site, a complex of high mannose residues, the bridging sheet, and the V3 loop. However, HIV-infected individuals are able to produce both neutralizing Abs that target additional epitopes and "non-neutralizing" Abs that block virus replication through pathways other than that mediated by pH-independent virus/cell fusion. These latter "non-neutralizing" Abs inhibit viral replication through a variety of mechanisms such as those mediated by Fc receptor-bearing cells and by complement. Based on these findings, we propose to focus efforts on identifying new protective human mAbs, i.e., both "conventional" neutralizing mAbs specific for previously unrecognized envelope (Env) epitopes, and human mAbs that inhibit virus replication via "non-neutralizing" pathways. For this, hybridomas will be generated from cells of US and Cameroon subjects infected with HIV strains carrying clade B and A Envs, respectively. Three new screening methods will be used for mAb selection, and a variety of methods will be employed to test the ability of the new mAbs to inhibit virus replication. The work is divided into three aims: 1) Identification of new neutralizing mAbs which target previously unrecognized epitopes, and selection of mAbs with virus inhibitory activities that function through "non-neutralizing" pathways. Pseudoviruses, Env-expressing cells and gp120 reagents will be used in several screening assays, each chosen to maximize the different types and cross-reactivity of mAbs to be selected, and to determine if there are epitopes that are uniquely or preferentially targeted by newly transmitted viruses. 2) Delineation of the inhibitory activities of these mAbs, of their breadth against viruses and pseudoviruses from multiple clades, and of the different patterns of reactivity between the clade B- and A- derived mAbs. These comparisons, together with descriptions of the immunologic nature and specificities of the mAbs, will provide the first comprehensive and systematic information about the characteristics of mAbs with different protective activities. And, 3) Mapping of the epitopes targeted by the new mAbs. Immunologic, virologic and physicochemical techniques will be used to delineate mAb epitopes, the specific interactions between mAb and Env, and quaternary Env structures targeted by mAbs. The reagents generated and the knowledge gained will illuminate mechanisms of virus neutralization and pathways that interrupt virus replication, and will inform the design of reagents for use in active immunization (vaccines), passive immunization, and immunotherapy.

Public Health Relevance

The work described in this application is designed to provide fundamental scientific information about the structure of HIV which will help to design and develop an effective HIV vaccine. This work may, as well, lead to the development of antibodies that can be produced in test tubes and could be administered to humans exposed to HIV in order to prevent HIV infection. These antibodies could also be used to develop products to treat HIV infection when used in conjunction with anti-retroviral drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL059725-15S1
Application #
8759759
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Mitchell, Phyllis
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2015-11-30
Support Year
15
Fiscal Year
2014
Total Cost
$799,591
Indirect Cost
$310,499
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Zolla-Pazner, Susan (2014) A critical question for HIV vaccine development: which antibodies to induce? Science 345:167-8
Zolla-Pazner, Susan; deCamp, Allan; Gilbert, Peter B et al. (2014) Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLoS One 9:e87572
Spurrier, Brett; Sampson, Jared; Gorny, Miroslaw K et al. (2014) Functional implications of the binding mode of a human conformation-dependent V2 monoclonal antibody against HIV. J Virol 88:4100-12
Andrabi, Raiees; Williams, Constance; Wang, Xiao-Hong et al. (2013) Cross-neutralizing activity of human anti-V3 monoclonal antibodies derived from non-B clade HIV-1 infected individuals. Virology 439:81-8
Alam, S Munir; Liao, Hua-Xin; Tomaras, Georgia D et al. (2013) Antigenicity and immunogenicity of RV144 vaccine AIDSVAX clade E envelope immunogen is enhanced by a gp120 N-terminal deletion. J Virol 87:1554-68
Perez, Lautaro G; Zolla-Pazner, Susan; Montefiori, David C (2013) Antibody-DEPENDENT, FcýýRI-mediated neutralization of HIV-1 in TZM-bl cells occurs independently of phagocytosis. J Virol 87:5287-90
Zolla-Pazner, Susan; deCamp, Allan C; Cardozo, Timothy et al. (2013) Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLoS One 8:e53629
Mayr, Luzia M; Cohen, Sandra; Spurrier, Brett et al. (2013) Epitope mapping of conformational V2-specific anti-HIV human monoclonal antibodies reveals an immunodominant site in V2. PLoS One 8:e70859
Gorny, Miroslaw K; Pan, Ruimin; Williams, Constance et al. (2012) Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals. Virology 427:198-207
Wu, Xueling; Changela, Anita; O'Dell, Sijy et al. (2011) Immunotypes of a quaternary site of HIV-1 vulnerability and their recognition by antibodies. J Virol 85:4578-85

Showing the most recent 10 out of 71 publications