Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors1,2,3. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs)4,5,6,7. However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4+ T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies8. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.
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These studies were supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants R01 AI067031 (M.A.) and PO1 AI074415 (M.A. and T.M.A.), and by the Doris Duke Charitable Foundation (M.A.). This project was funded in whole or in part with federal funds from the National Cancer Institute (NIH) under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. S.I.K. is a recipient of a Wellcome Trust Senior Clinical Fellowship and M.A. is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. We thank Microsoft Research, the Bill & Melinda Gates Foundation, the Mark and Lisa Schwartz Foundation and the Phillip T. and Susan M. Ragon Foundation for their support.
The authors declare no competing financial interests.
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Alter, G., Heckerman, D., Schneidewind, A. et al. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476, 96–100 (2011). https://doi.org/10.1038/nature10237
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