%A Peppa,Dimitra %A Pedroza-Pacheco,Isabela %A Pellegrino,Pierre %A Williams,Ian %A Maini,Mala K. %A Borrow,Persephone %D 2018 %J Frontiers in Immunology %C %F %G English %K Natural Killer cells,hcmv,HIV-1,Adaptive,PLZF %Q %R 10.3389/fimmu.2018.00474 %W %L %M %P %7 %8 2018-March-16 %9 Original Research %+ Dimitra Peppa,Division of Infection and Immunity, University College London (UCL),United Kingdom,dimitra.peppa@ndm.ox.ac.uk %+ Dimitra Peppa,Nuffield Department of Clinical Medicine, University of Oxford,United Kingdom,dimitra.peppa@ndm.ox.ac.uk %+ Dimitra Peppa,Centre for Sexual Health and HIV Research, University College London (UCL),United Kingdom,dimitra.peppa@ndm.ox.ac.uk %# %! Adaptive NK cells in HIV-1 infection %* %< %T Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection %U https://www.frontiersin.org/articles/10.3389/fimmu.2018.00474 %V 9 %0 JOURNAL ARTICLE %@ 1664-3224 %X 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.