Blockage of CD59 diminishes infectivity of HIV-1-positive plasma in vitro and in vivo (53.21)

Abstract

Abstract Numerous vaccination trials have been conducted to induce neutralizing antibodies (nAbs) against HIV-1. However, high levels of Abs, including nAbs and non-nAbs, mount in vast majority of HIV-1 infected subjects, yet fail to control virus proliferation or protect patients from developing AIDS, indicating that HIV-1 virions can escape Ab immunity. Recent studies have shown that regulators of complement activation (RCA) including CD59 present on the viral envelope (Env) confer resistance to Ab-dependent complement-mediated lysis (ADCML), which may explain why HIV-1 is not neutralized or lysed even in the presence of high titer of anti-Env Abs. Here, we report that blockage of CD59 on HIV-1 Env in infected patient plasma by BRIC229, a widely used CD59-blocking Ab, or rILYd4, a novel CD59 inhibitor derived from bacterial toxin intermedilysin domain 4, significantly reduces infectivity of HIV-1-positive plasma in vitro (H9 cells) and in vivo (SCID mice reconstituted with human peripheral blood mononuclear cells or PBMCs). Similarly, BRIC229 and rILYd4 significantly enhanced ADCML of HIV-1-infected H9 cells and HIV-1-bound erythrocytes in the presence of patient plasma as a source of both complement and anti-HIV-1 Env Abs. All plasma samples from 7 HIV-1-infected patients examined contained high titer of anti-HIV-1 Env Abs. Our data suggest that blockage of CD59 on the surface of HIV-1 virions and infected cells represents a novel therapeutic approach to combat HIV-1/AIDS pandemic.