1. Reviewer #3 (Public Review):

    In the paper by Victorino et al., the authors describe the role for transcription factor HIF1a in NK cells during MCMV infection. They clearly demonstrate that HIF1a-deficiency results in impaired viral control, with a major effect visible in the impacted expansion of MCMV-specific NK cells. The paper brings novelty to the field as the role of HIF1a has not been addressed in NK cells in the course of viral infection.

    The conclusions of the paper are mostly well supported by the data however there are still some aspects of the study that need clarification and extension.

    i) It remains unclear what induces HIF1a expression during MCMV infection.

    ii) The authors could speculate on the mechanisms of how HIF1a promotes repression of Bim during MCMV infection?

    iii) The lack of expression of HIF1a glycolytic genes in HIF1a-deficient NK cells may not be surprising but it is very clear and convincing and supports the idea that HIF1a promotes survival of cells by promoting glycolysis. However, the study would benefit with a formal proof of this metabolic adaptation in the context of MCMV infection.

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  2. Reviewer #2 (Public Review):

    In this manuscript, the authors analyzed the role of HIF1a in NK cells in a variety of settings, including viral infection. HIF1a deficient NK cells appear to be mostly functional in terms of effector functions and ability to proliferate with only subtle differences with WT NK cells. This was also observed in HIF1a deficient Ly49H+ NK cells, yet in vivo Ly49H expansion is reduced in HIF1a KO mice. Response to IL-2 demonstrate that despite similar proliferation rate NK cell numbers were reduced indicating to the authors an NK cell survival issue. This was confirmed by measuring Bim and Bcl2, which were respectively decreased and increased. Increased cell death of HIF1a deficient NK cells during MCMV was confirmed. Mechanistically, the authors found that cell death was autophagy independent but due to an impaired glycolytic activity. The author concluded that in the absence of HIF1a, NK cells had an increase apoptosis due to abnormal glucose metabolism. Overall, the experiments are well executed and are logical and the conclusions are supported by the data presented.

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  3. Reviewer #1 (Public Review):

    The manuscript by Victorino et al. describes the role of the metabolic adaptor hypoxia inducible factor-1α (HIF1α) in NK cells during viral infection. They first showed that NK cells constitutively express HIF1α and it is upregulated by murine cytomegalovirus (MCMV) infection. Using HIF1α KO mice, they provided evidence that HIF1α is dispensable for normal NK cell development, but important for NK cell dependent virus control and morbidity, NK cell number and their expansion. Although the lack of HIF1α affects the NK cell dependent virus control, it appears that HIF1α is not required for NK cell effector functions. In spite of the fact that proliferation of NK cells in HIF1α KO was not affected, their ultimate number was reduced due to the upregulation of pro-apoptotic protein Bim coupled with increased caspase activity and impaired glucose metabolism. As authors pointed out, the data presented in this manuscript are in sharp contrast to previous finding on the role of HIF1α in NK cell responses to tumors, suggesting the impact of tumor microenvironment.

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  4. Evaluation Summary:

    By using mice lacking the hypoxia inducible factor-1α (HIF1α) in NK cells, the study unravels a previously unknown function of this transcription factor in virus control by NK cells. Mechanistically, the authors provided evidence that HIF1α supports survival of NK cells through an efficient glucose metabolism required for optimal NK cell response to viral infection.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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