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J Virol. 2019 Jul 3. pii: JVI.00933-19. doi: 10.1128/JVI.00933-19. [Epub ahead of print]

HLA-F on autologous HIV infected cells activates primary NK cells expressing the activating killer immunoglobulin-like receptor KIR3DS1.

Author information

Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC, Canada.
Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
Department of Family Medicine, Université de Montréal, Montreal, QC, Canada.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC, Canada
Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.
Division of Clinical Immunology, McGill University Health Centre, Montreal, QC, Canada.


HIV-exposed seronegative KIR3DS1 homozygotes have a reduced risk of HIV infection. HLA-F is the ligand for the activating NK cell receptor (NKR) KIR3DS1. HLA-F is expressed on HIV-infected CD4 T cells. Co-culture of sorted, HIV-infected CD4- (siCD4-) T cells with NK cells activated a higher frequency of KIR3DS1+ than KIR3DS1- NK cells from KIR3DS1 homozygotes to elicit anti-HIV functions such as CCL4, IFN-γ and CD107a expression. This was the case whether KIR3DS1+/- NK cells were analyzed inclusively or exclusively by gating out NK cells co-expressing the NKRs, KIR2DL1/L2/L3, 3DL2, KIR2DS1/S2/S3/S5, NKG2A and ILT2. Blocking the interaction of HLA-F on siCD4- cells with KIR3DS1 on exclusively gated KIR3DS1+ NK cells with KIR3DS1-Fc chimeric protein or an HLA-F specific monoclonal antibody, reduced the frequency of activated KIR3DS1+ cells compared to control conditions. KIR3DS1+ NK cell activation by HIV-infected CD4 cells may underlie the reduced risk of KIR3DS1 homozygotes to HIV infection.IMPORTANCE This manuscript investigates a mechanism that may underly epidemiological studies showing that carriage of the KIR3DS1 homozygous genotype is more frequent among HIV exposed seronegative subjects than among HIV susceptible individuals. Carriage of this genotype is associated with a reduced risk of HIV infection. The protective mechanism involves the interaction of HLA-F on CD4 cells infected with replication competent HIV with the activating NK receptor, KIR3DS1. This interaction leads to the activation of KIR3DS1+ NK cells for secretion of cytokines and chemokines with anti-HIV activity. Among these is the secretion of CCL4, which binds and blocks CCR5, the co-receptor for HIV entry of HIV into new target cells. In the setting of an exposure to HIV, incoming HIV-infected cells expressing HLA-F rapidly activate KIR3DS1+ NK cells to elicit anti-HIV activity. Exclusive gating strategies and blocking experiments support the notion that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cell functions.


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