A monoclonal antibody against lymphocyte function-associated antigen-1 decreases HIV-1 replication by inducing the secretion of an antiviral soluble factor

Abstract

BackgroundLymphocyte 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.MethodsTo 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.ResultsOur 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.ConclusionsThese 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.

The CD8+T Cell Noncytotoxic Antiviral Responses

“…Another way of enhancing CNAR is the treatment of PBMC with an LFA-1 antibody (section IV.C). It binds to CD8 + T cells and induces the production of a soluble factor with antiviral activity that is not any of the known anti-HIV cytokines or chemokines ( 180 ). In addition, thymosin α1 is a polypeptide derived from prothymosin-α (section IX.F) that enhances the secretion of antiviral soluble factors by lipopolysaccharide (LPS)-stimulated CD8 + T cells ( 181 ).…”

“…Factors that induce and enhance CNAR/CAF include the following: HIV replication ( 2 ) HLA concordance ( 33 ) Conserved retroviral motifs Activation: CD3 or PHA stimulation of CD8 + T cells IL-2 ( 121 , 160 , 161 ) CD40/CD40L-stimulated DCs ( 168 , 169 ) CD28 costimulation ( 121 ) Early ART treatment ( 31 , 162 , 175 ) IL-15 ( 153 , 173 ) IL-21 ( 110 ) Allogeneic mixed lymphocyte reaction ( 176 – 179 , 342 ) LFA-1 agonist antibody ( 180 ) Thymosin α1 ( 181 ) TLR7/8 agonists ( 182 ) Potential vaccine ( 64 ) …”

Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

“…It was therefore hypothesized that an anti-LFA-1 mAb could be used therapeutically against HIV-1 infection. Early studies indeed showed that an anti-LFA-1 mAb could reduce HIV-1 RNA in HIV-1 infected individuals (93), and more recently it was found to inhibit the cell-cell spread of infection (94). Cell-cell transmission of HIV-1 plays an important role in the propagation of infection in addition to cell-free infection of target cells, with some reporting that cell-cell infection could be the main route of HIV-1 infection (95)(96)(97).…”

Immunotherapy with Cell-Based Biological Drugs to Cure HIV-1 Infection

“…This mAb binds to both HIV-1 virions and CD8+ T cells and dendritic cells. However, it was demonstrated that it exerted anti-viral activity when bound to cells by inducing the production of an unidentified soluble factor that can inhibit HIV-1 replication [ 35 ]. The potential mechanisms of Cytolin ® have been investigated in an observational study on HIV-1 positive and negative subjects (NCT01048372).…”