Regaining of the functions of antibodies in HIV-1-infected individuals (38.2)

Abstract

Abstract Patients infected with HIV-1 are well known to mount a vigorous and sustained antibody (Ab) response to the virus. This response is also well known to have a limited effect on controlling virus proliferation or on protecting the patients from developing AIDS. This puzzling and frustrating phenomenon has been explained as the consequence of the incorporation and hijacking of regulators of complement activation (RCA) on HIV-1 virions and infected cells, which blocks Ab-dependent complement-mediated lysis (ADCML) of HIV-1 virions and infected cells by inhibiting the formation of the membrane attack complex (MAC) at the terminal stage of the complement activation cascades. Here, we report a potent and specific inhibitor of human CD59 (hCD59), one major member of human RCA. This inhibitor (designated rILYd4) was developed as a recombinant protein (114 aa) from the fourth domain of the bacterial toxin intermedilysin. We showed that rILYd4 in conjunction with polyclonal Abs to HIV-1 envelope, or with sera from HIV-1-infected patients at different stages of viral infection, efficiently abrogated hCD59 function and rendered complement-resistant HIV-1 virions including lab strains and primary isolates sensitive to ADCML. Toxicity assay using erythrocytes suggested rILYd4 has no or minimal non-specific cytotoxic effect. These results indicate that rILYd4 may represent a novel therapeutic agent for regaining the functions of Abs in HIV-1-infected patients to combat HIV-1 infection.