Antibody-Dependent Cellular Cytotoxicity via Humoral Immune Epitope of Nef Protein Expressed on Cell Surface

Abstract

Antibodies against various proteins of HIV type 1 (HIV-1) can be detected in HIV-1-infected individuals. We previously reported that the level of Ab response against one Nef epitope is correlated with HIV-1 disease progression. To elucidate the mechanism for this correlation, we examined Ab-dependent cellular cytotoxicity (ADCC) against target cells expressing Nef. We observed efficient cytotoxicity against Nef-expressing target cells in the presence of patient plasma and PBMCs. This ADCC activity was correlated with the dilution of plasma from HIV-1-infected patients. Addition of a specific synthetic peptide (peptide 31:FLKEKGGLE) corresponding to the Nef epitope reduced cell lysis to ∼50%. These results suggest that PBMCs of HIV-1-infected patients may exert ADCC via anti-Nef Abs in the patients’ own plasma and serve as a mechanism used by the immune system to regulate HIV-1 replication.

Antibody-Dependent Cell-Mediated Viral Inhibition Emerges after Simian Immunodeficiency Virus SIVmac251 Infection of Rhesus Monkeys Coincident with gp140-Binding Antibodies and Is Effective against Neutralization-Resistant Viruses

“…While the results of the present study suggest that the epitope specificity of ADCVI-mediating antibodies is probably broad, it is possible that some epitopes are better targets for ADCVI than are others (5,24,40,46). Epitopes that are masked by envelope glycosylation or that are more prone to mutation may, for example, be poorer targets for ADCVI.…”

Robust NK Cell-Mediated Human Immunodeficiency Virus (HIV)-Specific Antibody-Dependent Responses in HIV-Infected Subjects

“…Linear ADCC epitopes have been described for Env (3) and Nef (33) in HIV-1-infected longterm slow progressors (LTSP). LTSP subjects are typically persons who have been infected with HIV for more than 10 years and who remain healthy without anti-HIV treatment.…”

HIV Envelope-Specific Antibody and Vaccine Efficacy

“…The interaction between the Fc domain of the antibody and the corresponding receptor on effector cells triggers a series of events that lead to the destruction of the infected cell via cytotoxic granules (perforin, granzyme) or a death-receptor-dependent pathway (Fas/Fas ligand; TNF/TNFR) (de Saint Basile et al, 2010;Chavez-Galan et al, 2009). Most ADCC responses described in the literature are directed against the envelope protein (Env) (Ahmad & Menezes, 1996;Baum et al, 1996;Alsmadi & Tilley, 1998), although Nef (Yamada et al, 2004) and Tat (Florese et al, 2009) have also been shown to be ADCC targets. Additionally, a recent study in chronically infected subjects reported that Pol is an ADCC target, but this Pol-specific ADCC activity did not correlate with delayed HIV progression (Isitman et al, 2010).…”

“…Despite the potential efficacy of ADCC, little is known about specific epitopes recognized by antibodies able to mediate ADCC. Epitopes recognized by both antiEnv and anti-Nef antibodies that mediate ADCC have been described (Alsmadi et al, 1997;Yamada et al, 2004; Los Alamos National Laboratory Molecular Immunology Database). As discussed below, anti-Env antibodies that mediate ADCC have been associated with protection, however, whether anti-Nef or anti-Tat antibodies have an impact on natural infection is not known.…”