Abrogation of CD59 function restores activities of neutralizing and non-neutralizing antibodies in triggering antibody-dependent complement-mediated lysis of HIV-1 virions and provirus-activated latently infected cells (VIR1P.1125)

Abstract

Abstract Abrogation 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 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 ADCML enhancement 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 both laboratory-adapted R5, X4, and R5/X4 strains of HIV-1 and 6 primary isolates examined, as well as provirus-activated ACH-2 cells. In contrast, 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 their neutralizing activities, significantly enhanced specific ADCML of HIV-1 virions of both laboratory strains and primary isolates and provirus-activated latently infected cells. Thus, abrogation 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