Research Article: Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

Date Published: August 31, 2016

Publisher: Public Library of Science

Author(s): Matthew Zirui Tay, Pinghuang Liu, LaTonya D. Williams, Michael D McRaven, Sheetal Sawant, Thaddeus C Gurley, Thomas T. Xu, S. Moses Dennison, Hua-Xin Liao, Agnès-Laurence Chenine, S. Munir Alam, M. Anthony Moody, Thomas J. Hope, Barton F. Haynes, Georgia D. Tomaras, Daniel C. Douek.


Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

Partial Text

Antibodies are a critical part of the immune response against pathogens, and exert their protective functions via a multitude of mechanisms that involve both the Fv and Fc domains of the antibody. These include direct pathogen capture and neutralization, as well as mechanisms such as antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP) that engage other innate immune cells as effectors to clear infected host cells, immune complexes, and opsonized virus [1]. Apart from direct sequestration and destruction of pathogens, engagement of innate immune cells also influences the downstream adaptive immune response by stimulating the secretion of inflammatory mediators [2].

Substantial evidence suggests a role of Fc-receptor mediated antibody functions in protection against HIV-1 infection [3–12]. Here, we evaluated Fc-mediated HIV-1 virion internalization by primary monocytes. We demonstrated that HIV-1 envelope specific IgG and IgA can complex with infectious HIV-1 virions leading to phagocytosis by primary monocytes. The potency of virion internalization was modulated by antibody Fc, where IgG3 was the most potent, followed by IgG1, then IgA. Furthermore, we found that HIV-1 infection elicits mucosal IgG that can recognize infectious virions, providing proof of concept that these types of antibodies easily elicited by vaccination can provide partial blocking HIV-1 acquisition at mucosal surfaces. Further studies are needed to evaluate the potential protective and/or detrimental roles of this Fc-mediated antibody function at mucosal sites.




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