title: Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.
abstract: Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection.
  
  
  OBJECTIVE
  Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom.
authors: Hannah M
authors: HM
authors: Cheeseman
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom.
authors: Natalia J
authors: NJ
authors: Olejniczak
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom.
authors: Paul M
authors: PM
authors: Rogers
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom.
authors: Abbey B
authors: AB
authors: Evans
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom.
authors: Deborah F L
authors: DFL
authors: King
authors: Imperial College London, Department of Surgery, St. Mary's Hospital, London, United Kingdom.
authors: Paul
authors: P
authors: Ziprin
authors: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors: Hua-Xin
authors: HX
authors: Liao
authors: Duke Human Vaccine Institute, Department of Medicine, and Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors: Barton F
authors: BF
authors: Haynes
authors: Imperial College London, Department of Medicine, Section of Virology, Group of Mucosal Infection and Immunity, London, United Kingdom r.shattock@imperial.ac.uk.
authors: Robin J
authors: RJ
authors: Shattock
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000494:pharmacology*; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005260:Female; D015870:Gene Expression; D015483:HIV Antibodies / Q000096:biosynthesis / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008297:Male; D008954:Models, Biological; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D010413:Penis / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D012007:Rectum / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D046509:Tissue Culture Techniques
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D017452:Receptors, IgG
keywords: HIV vaccines; human immunodeficiency virus; mucosal immunity; neutralizing antibodies; nonneutralizing antibodies