Entering a new era of harnessing natural killer cell responses in HIV infection

Abstract

Natural killer (NK) cells play a key role in antiviral and tumour are characterised by epigenetic changes, stochastic loss of expression immunity. In the setting of HIV infection, accumulating evidence implicates NK cells as critical contributors to immune control of HIV. In particular, indirect NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been linked to vaccine-induced protective immunity against HIV infection and phenotypes of viral control [1]. With emerging knowledge of specialised subpopulations and increased understanding of NK cell memory and immunoregulatory properties, new prospects have emerged to address remaining challenges in the field of HIV; namely control of persistent inflammation and comorbidity in treated infection, development of an effective vaccine and safe and widely available strategies for a ‘functional cure’. NK cells recognise stress signals, cancer transformation or infection with immediate effector function achieved via expression of a wide array of receptors and integration of finely attuned signals. In addition to cytotoxic elimination of target cells, NK cells are potent producers of cytokines and chemokines and can promote or suppress adaptive and innate immune responses. NK cell pleiotropic functions and remarkable effector agility makes them ideal candidates for immunotherapeutic interventions. Several approaches, including the development of chimeric antigen receptor (CAR) NK cells, show substantial promise in cancer trials and can be translated to direct and augment NK cell responses to improve HIV control. Some examples include activation of NK cell through blocking inhibitory signalling thoughNKG2A and inhibitory KIRS or activation through TLR agonists and IL15 to increase NK cell antiviral responses [2] (Fig. 1). In addition to strategies boosting NK cell effector capability, the adoptive transfer of haploidentical NK cell infusion following IL-2 stimulation is being evaluated for HIV treatment (clinical trial NCT03346499). Although traditionally considered as innate effector cells, the recognition that NK cell subsets can clonally expand and form long-lasting pools of memory-like cells in response to viral infection and/or immunisation represents a major advance in the field of NK cell research. In humans adaptive NK cells have been described in the context of CMV infection, leading to a substantial and long-lasting increase in NKG2C+ NK cells displaying preferential binding to some HLA-E presented CMV peptides [3]. Further subpopulations of adaptive NK cells