Abstract
Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A− phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF− NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control.
Highlights
Natural killer (NK) cells are a diverse subset of innate lymphocytes that play a key effector role in antiviral defense, especially against herpesviruses [1], and tumor surveillance [2], and have important immunoregulatory functions [3]
Human cytomegalovirus (HCMV) seropositivity in both HIV+ and HIV− subjects was associated with a higher frequency of CD56dim NK cells expressing NKG2C and lower expression of NKG2A compared with HCMV seronegative controls (Figure 1D)
This study demonstrates that viremic HIV-1-infected patients manifest phenotypic and functional perturbations in their NK cell compartment consistent with an adaptive reconfiguration driven in part by underlying co-infection with HCMV, an almost ubiquitous pathogen in HIV-1-infected cohorts and a recognized cofactor associated with ongoing immune activation
Summary
Natural killer (NK) cells are a diverse subset of innate lymphocytes that play a key effector role in antiviral defense, especially against herpesviruses [1], and tumor surveillance [2], and have important immunoregulatory functions [3]. Human cytomegalovirus (HCMV) infection has been linked with the identification of adaptive or memory-like NK cells in humans These lasting expansions were originally characterized by higher frequencies of NKG2C+ NK cells in HCMV-seropositive individuals and/ or in the context of acute HCMV infection or reactivation [12, 13]. A degree of redundancy is evidenced by the detection of NK cell subsets sharing numerous phenotypic and functional attributes of adaptive NK cells in individuals independent of NKG2C or in the absence of NKG2C (KLRC2-deficient individuals) and in transplant recipients of NKG2C null grafts [16,17,18] These so-called adaptive NK cells share epigenetic similarities to cytotoxic CD8 T cells and are marked by DNA methylationdependent silencing of the transcription factor promyelocytic leukemia zinc (PLZF), as well as stochastic loss of expression of key proximal signaling molecules such as FcεRI-γ, spleen tyrosine kinase (SYK), or EWS/FLI1-activated transcript 2 [15, 19, 20]. Adaptive NK cells are functionally dichotomized, exhibiting reduced responsiveness to stimulation with IL-12/IL-18 and a bias toward Fc receptor-dependent functions and specialization in the immunosurveillance of infected cells, and may be important for HCMV control especially when T cell immunity is impaired [21]
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