Abstract
Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.
Highlights
Despite more than 30 years of intensive research, HIV still represents a global health problem with up to 37 million HIV-infected people worldwide in 2015
CD56dim Natural killer (NK) cells constitute more than 90% of the NK cells in the peripheral blood and they are able to induce apoptosis of virus-infected cells by the release of granzymes and perforin or binding of ligands (TRAIL, FasL) to their death receptors (TRAIL-R, FasR)
Immunological dysregulation of NK cell responses during retroviral infections Beside NK cell evasion mechanisms that are directly mediated by HIV-1 proteins or peptides, retrovirus infections can dysregulate molecules or cells of the immune system to circumvent NK cell activation
Summary
Despite more than 30 years of intensive research, HIV still represents a global health problem with up to 37 million HIV-infected people worldwide in 2015. (3) Functional cure with the intention to control HIV replication without using ART [24] Several of these approaches to induce HIV immune control are currently under investigation, like broadly neutralizing antibody therapies, usage of recombinant viral vectors to achieve induction of cytotoxic CD8+ T cells as well as genome editing or expansion and activation of virusspecific immune cells. Immunodeficiency virus (SIV) or MuLV, various nucleic acid intermediates are generated (reviewed in [26]), which might be potential targets for endosomal or cytoplasmic sensors Up to now, it is not completely understood, which PRRs are essential for the recognition of HIV or murine retroviruses and how this sensing further influences host immune responses. The carboxyl terminus and in particular the residues at positions 7 and 8 seem to be of specific relevance for IFNα/β
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