title: Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge.
abstract: Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans.
authors: Mucosal Infection & Immunity Group, Section of Infectious Diseases, Imperial College London, St. Mary's Campus, London, United Kingdom.
authors: Katja
authors: K
authors: Klein
authors: Ronald S
authors: RS
authors: Veazey
authors: Ranjit
authors: R
authors: Warrier
authors: Peter
authors: P
authors: Hraber
authors: Lara A
authors: LA
authors: Doyle-Meyers
authors: Viviana
authors: V
authors: Buffa
authors: Hua-Xin
authors: HX
authors: Liao
authors: Barton F
authors: BF
authors: Haynes
authors: George M
authors: GM
authors: Shaw
authors: Robin J
authors: RJ
authors: Shattock
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000276:immunology; D008253:Macaca mulatta; D012749:Sexually Transmitted Diseases / Q000517:prevention & control*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G
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