title: Env-2dCD4 S60C complexes act as super immunogens and elicit potent, broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1).
abstract: The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4(S60C) are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env-2dCD4(S60C) complexes described here are "super" immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4(60C). Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env-2dCD4(S60C) complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted.
authors.affiliation: HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Killick
authors.affiliation: HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Grant
authors.affiliation: HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Cerutti
authors.affiliation: HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa.
authors.forename: Alexio
authors.initials: A
authors.lastname: Capovilla
authors.affiliation: HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa. Electronic address: Maria.Papathanasopoulos@wits.ac.za.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Papathanasopoulos
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D004337:Drug Carriers / Q000378:metabolism*; D015483:HIV Antibodies / Q000097:blood*; D015497:HIV-1 / Q000276:immunology*; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D004337:Drug Carriers; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: Anti-CD4 responses; Broadly neutralizing antibodies; Env–2dCD4(S60C); HIV-1 vaccine immunogens; Preclinical testing