Abstract
Natural killer (NK) cells specialize in killing virally infected- or tumor cells and are part of the innate immune system. The activational state of NK cells is determined by the balance of incoming activating and inhibitory signals mediated by receptor-ligand binding with the target cell. These receptor-ligand bonds mainly consist of the killer immunoglobulin-like receptors (KIR), which are expressed at the cell surface of NK cells, and their ligands: the highly variable human leukocyte antigen -class I molecules (HLA). Absence of an inhibitory receptor-ligand bond lowers the NK cell activation threshold, whereas an activating receptor-ligand bond stimulates the cell, potentially overcoming this threshold and triggering NK cell activation. NK cells influence the course of infection as well as the acquisition of HIV-1. Several lines of evidence relate the activating NK cell receptor KIR3DS1, in the presence or absence of its putative ligand HLA-Bw4, with slower disease progression as well as resistance to HIV-1 infection. Overall, resistance to HIV-1 infection predominantly correlates with activating KIR/HLA profiles, consisting of e.g. activating KIRs, group B haplotypes, or inhibitory KIRs in absence of their ligands. Such a conclusion is less evident for studies of HIV-1 disease progression, with studies reporting beneficial as well as detrimental effects of activating KIR/HLA genotypes. It is likely that KIR/HLA association studies are complicated by the complexity of the KIR and HLA loci and their mutual interactions, as well as by additional factors like route of HIV exposure, immune activation, presence of co-infections, and the effect of anti-HIV-1 antibodies. One newly discovered NK cell activation pathway associated with resistance to HIV-1 infection involves the presence of an iKIR/HLA mismatch between partners. The absence of such an iKIR/HLA bond renders donor-derived allogeneic HIV-1 infected cells vulnerable to NK cell responses during HIV-1 transmission. Therefore, theoretically, HIV-1 would be eliminated before it has the chance to infect the autologous cells in the recipient. While this “alloreactive” NK cell mechanism is especially relevant to HIV transmission in monogamous couples, it would be interesting to investigate how it could influence resistance to HIV in other settings. The objective of this review is to summarize the knowledge about these autologous and alloreactive NK cell responses with regard to HIV-1 outcome.
Highlights
human immunodeficiency virus type 1 (HIV-1) is considered to be one of the most widespread viruses, with 37 million people globally living with HIV-1 in 2014 and prime endemic areas situated in South and East Sub-Saharan Africa [1]
In multiple in vivo and in vitro studies, the effect of KIR3DS1+ Natural killer (NK) cells in combination with human leukocyte antigen -class I molecules (HLA)-Bw4 on HIV-1 infection was seen to result in slower disease progression
Throughout the years, different cohorts have been assembled, consisting of such HIV-1 exposed uninfected individuals. These socalled exposed seronegatives (ESN) constitute an interesting population for the study of HIV-1 protective mechanisms in an attempt to develop HIV-1 preventive or curative therapies
Summary
HIV-1 is considered to be one of the most widespread viruses, with 37 million people globally living with HIV-1 in 2014 and prime endemic areas situated in South and East Sub-Saharan Africa [1]. Further research on the “missing self ” model revealed a mechanism called “licensing” or “education”, which takes place during NK cell maturation and profoundly influences the functionality of the matured NK cell This licensing process allocates functionality towards NK cells capable of creating a bond between iKIR and self-HLA during maturation (Fig. 1a). Absence of such a bond will result in incompetent NK cells called “hypo-responsive NK cells”. Licensing of KIR2DS1+ NK cells was paradoxically only attained in the absence of the corresponding HLA-C2 ligand, whereas presence of the HLA-ligand generated hypo-responsive NK cells This newly identified education mechanism complements the inhibitory counterpart in preventing autoimmunity and in recognition of altered HLA class I molecules by NK cells [34, 35]. Education of NK cells does not result in lifelong functionality, but will constantly adapt to the present cellular environment, meaning that NK cells who were once hypo-responsive can become functional again and vice versa [36, 37]
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