title: Blockage of CD59 Function Restores Activities of Neutralizing and Nonneutralizing Antibodies in Triggering Antibody-Dependent Complement-Mediated Lysis of HIV-1 Virions and Provirus-Activated Latently Infected Cells.
abstract: Both HIV-1 virions and infected cells use their surface regulators of complement activation (RCA) to resist antibody-dependent complement-mediated lysis (ADCML). Blockage of the biological function of RCA members, particularly CD59 (a key RCA member that controls formation of the membrane attack complex at the terminal stage of the complement activation cascades via all three activation pathways), has rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by anti-Env antibodies (Abs) or sera/plasma from patients at different stages of viral infection. In the current study, we used the well-characterized anti-HIV-1 neutralizing Abs (nAbs), including 2G12, 2F5, and 4E10, and non-nAbs, including 2.2C, A32, N5-i5, and N12-i15, to investigate whether the enhancement of ADCML by blockage of CD59 function is mediated by nAbs, non-nAbs, or both. We found that all nAbs and two non-nAbs (N5-i5 and A32) strongly reacted to three HIV-1 laboratory strains (R5, X4, and R5/X4), six primary isolates, and provirus-activated ACH-2 cells examined. In contrast, two non-nAbs, 2.2C and N12-i15, reacted weakly and did not react to these targets, respectively. After blockage of CD59 function, the reactive Abs, regardless of their neutralizing activities, significantly enhanced specific ADCML of HIV-1 virions (both laboratory strains and primary isolates) and provirus-activated latently infected cells. The ADMCL efficacy positively correlated with the enzyme-linked immunosorbent assay-reactive intensity of those Abs with their targets. Thus, blockage of RCA function represents a novel approach to restore activities of both nAbs and non-nAbs in triggering ADCML of HIV-1 virions and provirus-activated latently infected cells.
  
  
  OBJECTIVE
  There is a renewed interest in the potential role of non-nAbs in the control of HIV-1 infection. Our data, for the first time, demonstrated that blockage of the biological function of RCA members rendered both HIV-1 virions and infected cells sensitive to ADCML mediated by not only nAbs but also non-nAbs. Our results are significant in developing novel immune-based approaches to restore the functions of nAbs and non-nAbs in the circulation of HIV-1-infected individuals to specifically target and clear HIV-1 virions and infected cells. Our data also provide new insights into the mechanisms by which HIV-1 virions and infected cells escape Ab-mediated immunity and could aid in the design and/or development of therapeutic HIV-1 vaccines. In addition, a combination of antiretroviral therapy with RCA blockage, provirus activators, and therapeutic vaccines may represent a novel approach to eliminate HIV-1 reservoirs, i.e., the infected cells harboring replication-competent proviruses and residual viremia.
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical University, Wenzhou, Zhejiang, China Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lan
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Shepherd
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Ningjie
authors.initials: N
authors.lastname: Hu
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Byrd
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Tohti
authors.initials: T
authors.lastname: Amet
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Corlin
authors.initials: C
authors.lastname: Jewell
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Kounga
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical University, Wenzhou, Zhejiang, China andyu@iupui.edu jimingao@yahoo.com.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Wenzhou Medical University, Wenzhou, Zhejiang, China Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA andyu@iupui.edu jimingao@yahoo.com.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Yu
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D018957:CD59 Antigens / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D011533:Proviruses / Q000276:immunology*; D014771:Virion / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D018957:CD59 Antigens; D015483:HIV Antibodies; C051590:CD59 protein, human; D003165:Complement System Proteins