Abstract
There is growing interest in HIV-specific antibody-dependent cellular cytotoxicity (ADCC) as an effective immune response to prevent or control HIV infection. ADCC relies on innate immune effector cells, particularly NK cells, to mediate control of virus-infected cells. The activation of NK cells (i.e., expression of cytokines and/or degranulation) by ADCC antibodies in serum is likely subject to the influence of other factors that are also present. We observed that the HIV-specific ADCC antibodies, within serum samples from a panel of HIV-infected individuals induced divergent activation profiles of NK cells from the same donor. Some serum samples primarily induced NK cell cytokine expression (i.e., IFNγ), some primarily initiated NK cell expression of a degranulation marker (CD107a) and others initiated a similar magnitude of responses across both effector functions. We therefore evaluated a number of HIV-relevant soluble factors for their influence on the activation of NK cells by HIV-specific ADCC antibodies. Key findings were that the cytokines IL-15 and IL-10 consistently enhanced the ability of NK cells to respond to HIV-specific ADCC antibodies. Furthermore, IL-15 was demonstrated to potently activate “educated” KIR3DL1+ NK cells from individuals carrying its HLA-Bw4 ligand. The cytokine was also demonstrated to activate “uneducated” KIR3DL1+ NK cells from HLA-Bw6 homozygotes, but to a lesser extent. Our results show that cytokines influence the ability of NK cells to respond to ADCC antibodies in vitro. Manipulating the immunological environment to enhance the potency of NK cell-mediated HIV-specific ADCC effector functions could be a promising immunotherapy or vaccine strategy.
Highlights
The development of a safe and effective HIV vaccine is urgently needed
To evaluate this hypothesis we simultaneously evaluated sera samples obtained from a cohort of 32 antiretroviral therapy naive HIV-infected subjects for their ability to activate fresh natural killer (NK) cells in blood obtained from a single healthy donor in the presence of Env peptide or protein antigens
As HIV infection is associated with immune activation and perturbations of plasma cytokine levels [16], these samples often contain a suite of biologically active factors that can skew the antibody-dependent cellular cytotoxicity (ADCC) measurement
Summary
The development of a safe and effective HIV vaccine is urgently needed. Traditional HIV vaccine constructs have focused on the induction of broadly neutralizing antibodies (BnAbs) and cytotoxic T-lymphocytes (CTL) [1]. Several lines of evidence suggest that non-neutralizing HIV-specific antibodies could play an important role in preventing or controlling HIV infection These antibodies can bind to infected cells and recruit innate immune effector cells, such as natural killer (NK) cells, to lyse infected cells through antibody-dependent cellular cytotoxicity (ADCC). High levels of HIV-specific ADCC-competent antibodies were induced by this regimen, suggesting such responses may play a role in protective immunity [3,4]. This idea is supported by elegant passive transfer experiments in Rhesus macaques, which demonstrate decreased effectiveness of BnAbs no longer capable of eliciting antibody constant region (Fc)-dependent ADCC responses [5]. ADCC responses have been associated with protective outcomes against immunodeficiency viruses [6,7], in particular this has been observed in highly exposed seronegative intravenous drug users, HIV-infected elite controllers and vaccinated Rhesus macaques [8,9,10]
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