Induction of Fc-Mediated Effector Functions Against a Stabilized Inner Domain of HIV-1 gp120 Designed to Selectively Harbor the A32 Epitope Region.

Authors:
Maria L Visciano
Maria L Visciano
Institute of Human Virology Department of Microbiology and Immunology
Neelakshi Gohain
Neelakshi Gohain
Institute of Human Virology
Baltimore | United States
Dr Rebekah Sherburn, PhD
Dr Rebekah Sherburn, PhD
Mcmaster University
Dr.
Immunology, asthma, allery
Hamilton, Ontario | Canada
Chiara Orlandi
Chiara Orlandi
Institute of Human Virology
Robin Flinko
Robin Flinko
Institute of Human Virology
United States
Dr Amir Dashti, PhD
Dr Amir Dashti, PhD
Pasteur Institute of Iran
Assistant Proffesor
Immunology
Tehran, Tehran | Iran
George K Lewis
George K Lewis
Institute of Human Virology
United States
William D Tolbert
William D Tolbert
Institute of Human Virology Departments of Biochemistry and Molecular Biology of University of Maryland School of Medicine

Front Immunol 2019 2;10:677. Epub 2019 Apr 2.

Division of Vaccine Research of Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.

Recent clinical trials and studies using nonhuman primates (NHPs) suggest that antibody-mediated protection against HIV-1 will require α-HIV envelope humoral immunity beyond direct neutralization to include Fc-receptor (FcR) mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC). There is also strong evidence indicating that the most potent ADCC response in humans is directed toward transitional non-neutralizing epitopes associated with the gp41-interactive face of gp120, particularly those within the first and second constant (C1-C2) region (A32-like epitopes). These epitopes were shown to be major targets of ADCC responses during natural infection and have been implicated in vaccine-induced protective immunity. Here we describe the immunogenicity of ID2, an immunogen consisting of the inner domain of the clade A/E 93TH057 HIV-1 gp120 expressed independently of the outer domain (OD) and stabilized in the CD4-bound conformation to harbor conformational A32 region epitopes within a minimal structural unit of HIV-1 Env. ID2 induced A32-specific antibody responses in BALB/c mice when injected alone or in the presence of the adjuvants Alum or GLA-SE. Low α-ID2 titers were detected in mice immunized with ID2 alone whereas robust responses were observed with ID2 plus adjuvant, with the greatest ID2 and A32-specific titers observed in the GLA-SE group. Only sera from groups immunized in the presence of GLA-SE were capable of mediating significant ADCC using NKr cells sensitized with recombinant BaL gp120 as targets and human PBMCs as effectors. A neutralization response to a tier 2 virus was not observed. Altogether, our studies demonstrate that ID2 is highly immunogenic and elicits A32-specific ADCC responses in an animal host. The ID2 immunogen has significant translational value as it can be used in challenge studies to evaluate the role of non-neutralizing antibodies directed at the A32 subregion in HIV-1 protection.

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Source
https://www.frontiersin.org/article/10.3389/fimmu.2019.00677
Publisher Site
http://dx.doi.org/10.3389/fimmu.2019.00677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455405PMC
April 2019
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