NK cell activation and CD4 T cell α4β7 expression are associated with susceptibility to HIV-1

Kawthar Machmach; Kombo F. N'guessan; Rohit Farmer; Sucheta Godbole; Dohoon Kim; Lauren McCormick; Noemia S. Lima; Amy R. Henry; Farida Laboune; Isabella Swafford; Sydney K. Mika; Bonnie M. Slike; Jeffrey R. Currier; Leigh Anne Eller; Julie A. Ake; Sandhya Vasan; Merlin L. Robb; Shelly J. Krebs; Daniel C. Douek; Dominic Paquin-Proulx

doi:10.1172/JCI187992

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Machmach, K. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by N'guessan, K. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Lima, N. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Laboune, F. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

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¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Mika, S. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Slike, B. in: PubMed | Google Scholar |

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Currier, J. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Eller, L. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Ake, J. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Vasan, S. in: PubMed | Google Scholar |

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Robb, M. in: PubMed | Google Scholar |

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Krebs, S. in: PubMed | Google Scholar |

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Douek, D. in: PubMed | Google Scholar

¹US Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

²Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

³Viral Diseases Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, United States of America

Find articles by Paquin-Proulx, D. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI187992.
Copyright © 2025, Machmach et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published May 8, 2025 - Version history

We leveraged specimens from the RV217 prospective study that enrolled participants at high risk of HIV-1 acquisition to investigate how NK, conventional T cells, and unconventional T cells influence HIV-1 acquisition. We observed low levels of α4β7 expression on memory CD4 T cells and iNKT cells, two cell types highly susceptible to HIV-1 infection, in highly exposed seronegative (HESN) compared to highly exposed seroconverter (HESC) participants. NK cells from HESN had higher levels of α4β7 compared to HESC, presented a quiescent phenotype, and had a higher capacity to respond to opsonized target cells. We also measured translocated microbial products in plasma and found differences in phylum distribution between HESN and HESC that were associated with the immune phenotypes impacting the risk of HIV-1 acquisition. Finally, a logistic regression model combining features of NK cells activation, α4β7 expression on memory CD4 T cells, and Tbet expression by iNKT cells achieved the highest accuracy in identifying HESN and HESC participants. This immune signature comprised of increased α4β7 on cells susceptible to HIV infection combined with higher NK cells activation and lower gut homing potential could impact the efficacy of HIV-1 prevention strategies such as vaccines.

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NK cell activation and CD4 T cell α4β7 expression are associated with susceptibility to HIV-1

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NK cell activation and CD4 T cell α4β7 expression are associated with susceptibility to HIV-1

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