title: Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells.
abstract: Lifelong antiretroviral therapy (ART) for HIV-1 does not diminish the established latent reservoir. A possible cure approach is to reactivate the quiescent genome from latency and utilize immune responses to eliminate cells harboring reactivated HIV-1. It is not known whether antibodies within HIV-1-infected individuals can recognize and eliminate cells reactivated from latency through antibody-dependent cellular cytotoxicity (ADCC). We found that reactivation of HIV-1 expression in the latently infected ACH-2 cell line elicited antibody-mediated NK cell activation but did not result in antibody-mediated killing. The lack of CD4 expression on these HIV-1 envelope (Env)-expressing cells likely resulted in poor recognition of CD4-induced antibody epitopes on Env. To examine this further, cultured primary CD4(+) T cells from HIV-1(+) subjects were used as targets for ADCC. These ex vivo-expanded primary cells were modestly susceptible to ADCC mediated by autologous or heterologous HIV-1(+) serum antibodies. Importantly, ADCC mediated against these primary cells could be enhanced following incubation with a CD4-mimetic compound (JP-III-48) that exposes CD4-induced antibody epitopes on Env. Our studies suggest that with sufficient reactivation and expression of appropriate Env epitopes, primary HIV-1-infected cells can be targets for ADCC mediated by autologous serum antibodies and innate effector cells. The results of this study suggest that further investigation into the potential of ADCC to eliminate reactivated latently infected cells is warranted.
  
  
  OBJECTIVE
  An HIV-1 cure remains elusive due to the persistence of long-lived latently infected cells. An HIV-1 cure strategy, termed "shock and kill," aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. While recent research efforts have focused on reversing HIV-1 latency, it remains unclear whether preexisting immune responses within HIV-1(+) individuals can efficiently eliminate the reactivated cells. HIV-1-specific antibodies can potentially eliminate cells reactivated from latency via Fc effector functions by recruiting innate immune cells. Our study highlights the potential role that antibody-dependent cellular cytotoxicity might play in antilatency cure approaches.
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Australia.
authors.forename: Wen Shi
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Centre de Recherche du CHUM, Montreal, Quebec, Canada Department of Microbiology, Infectiology and Immunology, Université de Montreal, Montreal, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Australia.
authors.forename: Marit
authors.initials: M
authors.lastname: Lichtfuss
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jongwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bruno N
authors.initials: BN
authors.lastname: Melillo
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
authors.affiliation: Centre de Recherche du CHUM, Montreal, Quebec, Canada Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA Department of Medicine, Université de Montréal, Montreal, Quebec, Canada Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Centre de Recherche du CHUM, Montreal, Quebec, Canada Department of Microbiology, Infectiology and Immunology, Université de Montreal, Montreal, Quebec, Canada Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada andres.finzi@umontreal.ca skent@unimelb.edu.au.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Australia.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Parsons
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC, Australia Central Clinical School, Melbourne Sexual Health Centre and Department of Infectious Diseases, Monash University, VIC, Australia ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, VIC, Australia andres.finzi@umontreal.ca skent@unimelb.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
mesh_terms: D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014775:Virus Activation
chemical_list: D015483:HIV Antibodies