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.