Abrogation of human CD59 function regains neutralizing and non-neutralizing antibody functions in triggering complement-mediated virolysis of HIV-1 (154.7)

Abstract

Abstract Patients infected with HIV-1 are well known to mount a vigorous and sustained antibody (Ab) response to the virus, yet fail to control virus proliferation or protect them from developing AIDS. Recent studies have suggested that resistance of HIV-1-infected cells and virions to Ab-dependent complement-mediated lysis (ADCML) is dependent on regulators of complement activation (RCA), particularly CD59 that controls the formation of the membrane attack complex (MAC) at the terminal stage of the complement activation cascades via all three activation pathways. Abrogation of CD59 function renders HIV-1 virions and infected cells sensitive to ADCML. In the current study, we used the well-characterized anti-HIV-1 nAbs (2G12, 2F5, 4E10 and b12) and non-nAbs (5F3, A32 and F240) to investigate whether the enhancement of ADCML by inhibition of CD59 is mediated by nAbs, non-nAbs or both. We found that these Abs, regardless of their neutralizing activity, significantly enhanced ADCML of many HIV-1 lab strains and 6 primary isolates examined in the presence of CD59 blockers. Direct addition of CD59 blockers into plasma from 16 HIV-1-infected individuals triggered ADCML of endogenous plasma virions, and the effect correlated to Ab titers rather than Ab neutralizing activity, indicating that patient plasma Abs are able to recognize endogenous virions, and abrogation of CD59 may represent a novel approach to regain the function of both nAbs and non-nAbs naturally present in patient’s blood.