Sustained Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in SIV-Infected Macaques Correlates with Delayed Progression to AIDS

Abstract

Although several in vitro lines of evidence support the potential power of antibody-dependent cell-mediated cytotoxicity (ADCC) in controlling HIV infection, the role of ADCC in the pathogenesis of HIV infection in vivo remains uncertain. There are few studies to date that longitudinally determine the plasma ADCC activity in HIV-infected subjects. We sought to establish an SIV/macaque model to perform such a longitudinal study. In the rhesus macaque cohort studied here, three of five macaques (designated Group 1) maintained higher plasma ADCC activity for at least 1 year after inoculation with SIV/17E-Br. The ADCC activity of the two remaining macaques (Group 2) fell 12 weeks after inoculation. There were also differences in longitudinal measurements of anti-SIV envelope IgG titers and CD4 counts. Group 1 macaques maintained higher antienvelope IgG titers and higher CD4(+) T cell numbers as late as 60 weeks postinoculation, while Group 2 macaques had significantly lower titers at 1 year postinoculation and lower CD4(+) T cell counts by 30 weeks postinoculation. Our study shows a correlation between humoral response, ADCC activity, and disease progression (as measured by CD4(+) T cell counts). In these animals, ADCC activity is associated with delayed progression to AIDS. Further studies are underway to determine if ADCC is a protective immune response in SIV infection or if ADCC is a marker of intact cellular and humoral immune responses.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Several groups also published data suggesting the ability of NK cells to mediate ADCC decreases during HIV infection (11,14,17,22). The association of ADCC with slower disease progression was observed in the rhesus macaque SIV model: maintenance of ADCC activity was observed in slow progressing macaques, and lower plasma ADCC activity was observed in macaques with more rapidly progressing infections (6). Cumulatively, these studies suggest that ADCC could play a pivotal role in slowing disease progression.…”

“…Interest in ADCC has been stimulated by a series of observations implying the involvement of this immune response in the control and prevention of HIV infection. The potential for involvement of ADCC in controlling HIV infection was suggested by observations that Abs capable of mediating ADCC occur at higher titers in HIV-infected elite controllers than in viremic individuals (4), that ADCC Abs in slow progressors (SPs) target a broader range of epitopes than do ADCC Abs from non-SPs (5), and that higher ADCC activity is retained in rhesus macaques with slowly progressing infections with SIV compared with macaques with rapidly progressing infections (6). Furthermore, the potential ability of ADCC to prevent HIV infection was demonstrated by elegant passive-transfer experiments performed in rhesus macaques.…”

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).…”

Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation

“…Individuals with slow progressing HIV infections also tend to exhibit ADCC-mediating antibodies against a broader range of viral epitopes [9]. Furthermore, a study in SIV-infected macaques linked sustained plasma ADCC activity to slower disease progression [10]. While these studies focused on the ability of anti-viral antibodies to mediate ADCC, other investigators have examined the ability of effector cells, such as natural killer (NK) cells, from HIV-infected individuals to mediate ADCC.…”