During their lifetime, over half the world’s population will experience chronic
viral infection or cancer, both of which involve evasion of host immunity. We have
within us immune cells called natural killer (NK) cells that constantly survey our
tissues to detect and eliminate transformed and infected cells. Thus, they have a
critical role in preventing cancer and containing virus infection. Although most
viruses only disrupt our lives transiently, if at all, some viruses establish life-long
persistent infection. Human cytomegalovirus (HCMV) is a common herpesvirus
infecting most of the adult population and although relatively innocuous in healthy
individuals, HCMV infection or reactivation has an enormous impact on the human
immune system, poses serious health risks to the immunocompromised, and is an
important cofactor driving ongoing immune activation in people living with HIV
(PLWH). One outcome of HCMV infection is emergence of a stable differentiated
population of phenotypically and functionally adapted NK cells exhibiting a form of
memory. While mechanisms that create adapted NK cells in vivo remain enigmatic,
exposure to HCMV is the one common factor underlying their presence. Exploring
basic molecular mechanisms governing NK cell-mediated immunity can inform cell-based
treatment strategies against virus infection or cancer. As chronic HIV-1
infection amplifies HCMV-driven accumulation of adaptive NK cells, we studied
whether NK cell adaptation to HCMV infection functionally impacts their natural and antibody-dependent cytotoxic functions in this setting. Although factors
present during HCMV infection augmented NK cell activity, we found no evidence
that NK cells acquire superior cytotoxic function or capacity for interferon-γ
secretion in response to target cells following adaptation to HCMV infection.
However, HCMV-driven NK cell adaptation in HIV-1 infection paralleled increased
expression of TIGIT, an inhibitory immune checkpoint receptor, on NK cells. As
chronic virus infection contributes to effector cell dysfunction, punctuated by
increased expression of inhibitory immune checkpoint receptors, it is important to
unravel the mechanisms by which viruses affect regular NK cell functions to either
prevent dysfunction or introduce disease-appropriate mediators to invigorate NK
cell responses. Understanding basic molecular mechanisms governing NK cell-mediated
immunity will inform new strategies to optimize our immune system
capacities