Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Abstract

With the recent demonstration in the RV144 Thai trial that a vaccine regimen that does not elicit neutralizing antibodies or cytotoxic T lymphocytes may confer protection against human immunodeficiency virus type 1 (HIV-1) infection, attention has turned to nonneutralizing antibodies as a possible mechanism of vaccine protection. In the current study, we evaluated the kinetics of the antibody-dependent cell-mediated cytotoxicity (ADCC) response during acute and chronic SIVmac251 infection of rhesus monkeys. We first adapted a flow cytometry-based ADCC assay, evaluating the use of different target cells as well as different strategies for quantitation of activated natural killer (NK) cells. We found that the use of SIVmac251 Env gp130-coated target cells facilitates analyses of ADCC activity with a higher degree of sensitivity than the use of simian immunodeficiency virus (SIV)-infected target cells; however, the kinetics of the measured responses were the same using these different target cells. By comparing NK cell expression of CD107a with NK cell expression of other cytokines or chemokine molecules, we found that measuring CD107a expression is sufficient for evaluating the anti-SIV function of NK cells. We also showed that ADCC responses can be detected as early as 3 weeks after SIVmac251 infection and that the magnitude of this antibody response is inversely associated with plasma viral RNA levels in animals with moderate to high levels of viral replication. However, we also demonstrated an association between NK cell-mediated ADCC responses and the amount of SIVmac251 gp140 binding antibody that developed after viral infection. This final observation raises the possibility that the antibodies that mediate ADCC are a subset of the antibodies detected in a binding assay and arise within weeks of infection.

Antibody-Dependent Cellular Cytotoxicity against Primary HIV-Infected CD4+T Cells Is Directly Associated with the Magnitude of Surface IgG Binding

“…However, these results are potentially consistent with those of a recent a study by Sun et al that showed a correlation between NK cell-mediated ADCC and titers of SIV mac251 gp140 binding antibody in the first 14 weeks of rhesus macaque SIV infection (44). Although it is unclear exactly how many antibody molecules must bind to an infected cell to trigger degranulation of an NK cell, most estimates predicted that this number was relatively small.…”

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

“…Fc-mediated effector functions were found to inversely correlate with viral loads or disease progression in simian immunodeficiency virus (SIV)-infected macaques (39)(40)(41) as well as in HIV-1-infected individuals (42)(43)(44)(45)(46). Furthermore, analysis of correlates of immune protection in the recent RV144 vaccine trial suggested that high levels of ADCC-mediating Abs correlated with decreased HIV-1 acquisition when combined with low plasma IgA anti-Env antibody levels (28,47).…”

Comparison of Antibodies That Mediate HIV Type 1 gp120 Antibody-Dependent Cell-Mediated Cytotoxicity in Asymptomatic HIV Type 1-Positive Men and Women

“…Recent studies in primates demonstrate that ADCC antibodies arise early after infection, 35 while neutralizing antibodies, which are generally clade specific, arise later in HIV-1 disease progression. Macaque studies indicate that ADCC antibodies have a broader range of activity than neutralizing antibodies.…”