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

  • Parsons M
  • Tang C
  • Jegaskanda S
  • et al.
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There is much interest in the potential of Ab-dependent cellular cytotoxicity (ADCC) to slow disease progression following HIV infection. Despite several studies demonstrating a positive association between ADCC and slower disease progression, it is possible that continued stimulation of NK cells by ADCC during chronic HIV infection could render these cells dysfunctional. Indeed, ac-tivation of NK cells by ADCC results in matrix metalloproteinase–induced reductions in CD16 expression and activation refractory periods. In addition, ex vivo analyses of NK cells from HIV-infected individuals revealed other alterations in phenotype, such as decreased expression of the activating NKp46 receptor that is essential for NK-mediated antitumor responses and immunity from infection. Because NKp46 shares a signaling pathway with CD16, we hypothesized that activation-induced downregulation of both receptors could be controlled by a common mechanism. We found that activation of NK cells by anti-HIV or anti-CD16 Abs resulted in NKp46 downregulation. The addition of a matrix metalloproteinase inhibitor attenuated NKp46 downregulation following NK cell activation by anti-HIV Abs. Consequently, these results suggest that continued stimulation through CD16 has the potential to impair natural cytotoxicity via attenuation of NKp46-dependent signals. The Journal of Immunology, 2014, 192: 308–315. A n urgent need exists for novel prophylactic vaccine constructs against HIV, as well as immunotherapeutic interventions to target reactivated latent viral reser-voirs. There is increased interest in using NK cell–mediated Ab-dependent cellular cytotoxicity (ADCC) for such prophylactic and therapeutic purposes (1–3). Interest in ADCC has been stimulated by a series of observations implying the involvement of this im-mune 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 ma-caques with rapidly progressing infections (6). Furthermore, the potential ability of ADCC to prevent HIV infection was demon-strated by elegant passive-transfer experiments performed in rhesus macaques. Indeed, alteration of the b12 broadly neutralizing Ab, so that it did not mediate interactions with C region receptors, de-creased the ability of the Ab to confer protection to rhesus ma-caques challenged with chimeric simian-HIV (7). Furthermore, the recently completed RV144 vaccine trial, which was modestly pro-tective in the absence of strong broadly neutralizing Ab or cytotoxic T cell responses, induced Abs capable of mediating ADCC that may have been related to the observed protection (8–10). Despite the immense interest in using ADCC for therapeutic purposes, it should be noted that NK cells exhibit extensive phenotypic alter-ations and dysfunction during HIV infection (11–22). However, it is unclear whether chronic activation of NK cells via ADCC could contribute to this disease-related dysfunction. Upon ex vivo analyses, NK cells from HIV-infected individuals exhibit altered phenotype, function, and subset distribution (11– 22). Infection with HIV was observed to coincide with the ap-pearance of a hypofunctional CD16 + CD56 2 subset and a decrease




Parsons, M. S., Tang, C.-C., Jegaskanda, S., Center, R. J., Brooks, A. G., Stratov, I., & Kent, S. J. (2014). Anti-HIV Antibody-Dependent Activation of NK Cells Impairs NKp46 Expression. The Journal of Immunology, 192(1), 308–315.

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