title: A novel trifunctional IgG-like bispecific antibody to inhibit HIV-1 infection and enhance lysis of HIV by targeting activation of complement.
abstract: BACKGROUND
  The complement system is not only a key component of innate immunity but also provides a first line of defense against invading pathogens, especially for viral pathogens. Human immunodeficiency virus (HIV), however, possesses several mechanisms to evade complement-mediated lysis (CoML) and exploit the complement system to enhance viral infectivity. Responsible for this intrinsic resistance against complement-mediated virolysis are complement regulatory membrane proteins derived from the host cell that inherently downregulates complement activation at several stages of the cascade. In addition, HIV is protected from complement-mediated lysis by binding soluble factor H (fH) through the viral envelope proteins, gp120 and gp41. Whereas inhibition of complement activity is the desired outcome in the vast majority of therapeutic approaches, there is a broader potential for complement-mediated inhibition of HIV by complement local stimulation.
  
  
  OBJECTIVE
  Our previous studies have proven that the complement-mediated antibody-dependent enhancement of HIV infection is mediated by the association of complement receptor type 2 bound to the C3 fragment and deposited on the surface of HIV virions. Thus, we hypothesize that another new activator of complement, consisting of two dsFv (against gp120 and against C3d respectively) linked to a complement-activating human IgG1 Fc domain ((anti-gp120 x anti-C3d)-Fc), can not only target and amplify complement activation on HIV virions for enhancing the efficiency of HIV lysis, but also reduce the infectivity of HIV through blocking the gp120 and C3d on the surface of HIV.
  
  
  METHODS
  Our hypothesis was tested using cell-free HIV-1 virions cultivated in vitro and assessment of virus opsonization was performed by incubating appropriate dilutions of virus with medium containing normal human serum and purified (anti-gp120 x anti-C3d)-Fc proteins. As a control group, viruses were incubated with normal human serum under the same conditions. Virus neutralization assays were used to estimate the degree of (anti-gp120 x anti-C3d)-Fc lysis of HIV compared to untreated virus.
  
  
  CONCLUSIONS
  The targeted complement activator, (anti-gp120 x anti-C3d)-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells.
authors.affiliation: Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, PR China.
authors.forename: Leili
authors.initials: L
authors.lastname: Jia
authors.forename: Yuanyong
authors.initials: Y
authors.lastname: Xu
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.forename: Shaofu
authors.initials: S
authors.lastname: Qiu
authors.forename: Ligui
authors.initials: L
authors.lastname: Wang
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Zhong
authors.forename: Weijing
authors.initials: W
authors.lastname: Liu
authors.forename: Yansong
authors.initials: Y
authors.lastname: Sun
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Hongbin
authors.initials: H
authors.lastname: Song
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000276:immunology*; D015536:Down-Regulation; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D003176:Complement C3; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G