title: A monoclonal antibody against lymphocyte function-associated antigen-1 decreases HIV-1 replication by inducing the secretion of an antiviral soluble factor.
abstract: BACKGROUND
  Lymphocyte Function-Associated Antigen-1 (LFA-1) likely plays a role in the pathogenesis of against HIV-1 and is known to facilitate cell-to-cell transmission of the virus. A monoclonal antibody specific for LFA-1 (Cytolin®) was evaluated as a potential therapeutic in pilot studies performed in the mid-1990s. These uncontrolled human studies suggested that administration of this anti-LFA-1 antibody to HIV-1 infected individuals could provide a modest benefit by decreasing circulating HIV-1 RNA and increasing CD4+ T cell counts. At the time, it was proposed that when bound to cytolytic T cells, the antibody inhibited lysis of activated CD4+ T cells. Given the renewed interest in monoclonal antibody therapy for HIV-1 infected individuals, we investigated possible mechanisms of action of this antibody in vitro.
  
  
  METHODS
  To assess whether this anti-LFA-1 antibody binds to HIV-1, a virus capture assay was performed. Binding of the antibody to cells was assessed using flow cytometry. Inhibition of HIV-1 replication was determined in culture by measuring the amount of p24 produced by ELISA. After co-culture of the antibody with peripheral blood mononuclear cells, supernatants were assayed for cytokines and chemokines using various immunoassays.
  
  
  RESULTS
  Our experiments demonstrate that anti-LFA-1 antibody binds to CCR5 and CXCR4 utilizing strains of HIV-1. It also binds to CD8+ T cells and dendritic cells. When bound to virus prior to infection, there is no decrease in HIV-1 replication, suggesting it does not directly inhibit viral replication via virus binding. When bound to cells, it does not inhibit lysis of CD4+ T cells, as was originally hypothesized. Binding to cells does appear to induce the production of a soluble factor that inhibits HIV-1 replication. We determined that this soluble factor was not any of the cytokines or chemokines with known anti-HIV-1 activity. Further, the antibody does not appear to induce any common immune modulating cytokines or chemokines.
  
  
  CONCLUSIONS
  These results suggest that one possible mechanism of action of this anti-LFA-1 antibody is to inhibit HIV-1 replication via the production of a soluble antiviral factor that is induced upon binding to cells.
authors.affiliation: Department of Medicine and Pathology, Harvard Medical School, Boston, MA, USA. jrychert@partners.org
authors.forename: Jenna
authors.initials: J
authors.lastname: Rychert
authors.forename: Lindsay
authors.initials: L
authors.lastname: Jones
authors.forename: Graham
authors.initials: G
authors.lastname: McGrath
authors.forename: Sue
authors.initials: S
authors.lastname: Bazner
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D053585:Virus Attachment; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D016207:Cytokines; D016655:HIV Core Protein p24; D016169:Lymphocyte Function-Associated Antigen-1