title: Poorly neutralizing cross-reactive antibodies against the fusion loop of West Nile virus envelope protein protect in vivo via Fcgamma receptor and complement-dependent effector mechanisms.
abstract: The human antibody response to flavivirus infection is dominantly directed against a cross-reactive epitope on the fusion loop of domain II (DII-FL) of the envelope (E) protein. Although antibodies against this epitope fail to recognize fully mature West Nile virus (WNV) virions and accordingly neutralize infection poorly in vitro, their functional properties in vivo remain less well understood. Here, we show that while passive transfer of poorly neutralizing monoclonal antibodies (MAb) and polyclonal antibodies against the DII-FL epitope protect against lethal WNV infection in wild-type mice, they fail to protect mice lacking activating Fcγ receptors (FcγR) and the complement opsonin C1q. Consistent with this, an aglycosyl chimeric mouse-human DII-FL MAb (E28) variant that lacks the ability to engage FcγR and C1q also did not protect against WNV infection in wild-type mice. Using a series of immunodeficient mice and antibody depletions of individual immune cell populations, we demonstrate that the nonneutralizing DII-FL MAb E28 does not require T, B, or NK cells, inflammatory monocytes, or neutrophils for protection. Rather, E28 treatment decreased viral load in the serum early in the course of infection, which resulted in blunted dissemination to the brain, an effect that required phagocytic cells, C1q, and FcγRIII (CD16). Overall, these studies enhance our understanding of the functional significance of immunodominant, poorly neutralizing antibodies in the polyclonal human anti-flavivirus response and highlight the limitations of current in vitro surrogate markers of protection, such as cell-based neutralization assays, which cannot account for the beneficial effects conferred by these antibodies.
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, MO 63110, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Vogt
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Dowd
authors.forename: Michael
authors.initials: M
authors.lastname: Engle
authors.forename: Robert B
authors.initials: RB
authors.lastname: Tesh
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D003429:Cross Reactions; D004195:Disease Models, Animal; D007116:Immunization, Passive; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D017452:Receptors, IgG / Q000276:immunology*; D012376:Rodent Diseases / Q000276:immunology / Q000517:prevention & control; D016019:Survival Analysis; D014759:Viral Envelope Proteins / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D017452:Receptors, IgG; D014759:Viral Envelope Proteins; D003165:Complement System Proteins