Abstract
The importance of innate immune cells in HIV-1 pathogenesis and protection has been highlighted by the role of natural killer (NK) cells in the containment of viral replication. Use of peripheral blood mononuclear cells (PBMC) in immunologic studies provides both HIV-1 target cells (ie. CD4+ T cells), as well as anti-HIV-1 effector cells, such as NK cells. In this study, NK and other immune cell populations were analyzed in HIV-negative donor PBMC for an impact on the anti-HIV activity of polyclonal and monoclonal antibodies. NK cell percentages were significantly higher in donor PBMC that supported lower levels of viral replication. While the percentage of NK cells was not directly associated with neutralization titers, NK cell-depletion significantly diminished the antiviral antibody activity by up to three logs, and polymorphisms in NK killer immunoglobulin receptor (KIR) and FcγRIIIa alleles appear to be associated with this affect. These findings demonstrate that NK cells and NK cell receptor polymorphisms may influence assessment of traditional HIV-1 neutralization in a platform where antibody is continuously present. This format appears to simultaneously assess conventional entry inhibition (neutralization) and non-neutralizing antibody-dependent HIV inhibition, which may provide the opportunity to delineate the dominant antibody function(s) in polyclonal vaccine responses.
Highlights
The results of the RV144 Phase III vaccine trial conducted in Thailand using a canarypox-vectored prime and gp120 envelope subunit boost, demonstrated modest protection (31.2% efficacy) against HIV-1 acquisition [1]
No significant difference was observed for CD4+ T cells and permissivity, there was a trend towards higher CD4+ T cells in donors with higher HIV-1 permissivity, as might be expected
We demonstrate that natural killer (NK) cells exert a critical influence on the assessment of antibody-mediated neutralization when using peripheral blood mononuclear cells (PBMC), and that killer immunoglobulin receptor (KIR) and FcR polymorphisms may contribute to this effect
Summary
The results of the RV144 Phase III vaccine trial conducted in Thailand using a canarypox-vectored prime and gp120 envelope subunit boost, demonstrated modest protection (31.2% efficacy) against HIV-1 acquisition [1]. The vaccine elicited anti-envelope binding antibodies, appear to have a relatively low capacity for neutralization in cell line models [2,3,4]. In the course of natural infection, HIV-1 can induce antibody responses to numerous well-characterized epitopes on the HIV-1 envelope glycoproteins [5]. These antibodies inhibit the virus by various mechanisms, including classic neutralization [6], antibodydependent cellular cytotoxicity (ADCC) [7], antibody dependent cell-mediated viral inhibition (ADCVI) [8], non-neutralizing HIV1 inhibition via Fc receptor binding (using macrophage or dendritic cell targets) [9] and antibody-dependent complementmediated HIV-1 inhibition or virolysis [10]. In hopes of eliciting sterilizing immunity, there has been a considerable effort to develop a vaccine that will elicit antibodies with some or all of these functions [19], and to standardize approaches to measure these antibodies [20]
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