HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells

Yetao Wang, Lawrence Lifshitz, Kyle Gellatly, Carol L. Vinton, Kathleen Busman-Sahay, Sean McCauley, Pranitha Vangala, Kyusik Kim, Alan Derr, Smita Jaiswal, Alper Kucukural, Patrick McDonel, Peter W. Hunt, Thomas Greenough, Jean Marie Houghton, Ma Somsouk, Jacob D. Estes, Jason M. Brenchley, Manuel Garber, Steven G. DeeksJeremy Luban

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Abstract

Human immunodeficiency virus 1 (HIV-1) infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer and other complications. These pathologies persist despite antiretroviral therapy. In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective antiretroviral therapy. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation and natural killer (NK) cell skewing towards an inflammatory state, with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results show that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.

Original languageEnglish (US)
Pages (from-to)274-286
Number of pages13
JournalNature Immunology
Volume21
Issue number3
DOIs
StatePublished - Mar 1 2020

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Wang, Y., Lifshitz, L., Gellatly, K., Vinton, C. L., Busman-Sahay, K., McCauley, S., Vangala, P., Kim, K., Derr, A., Jaiswal, S., Kucukural, A., McDonel, P., Hunt, P. W., Greenough, T., Houghton, J. M., Somsouk, M., Estes, J. D., Brenchley, J. M., Garber, M., ... Luban, J. (2020). HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells. Nature Immunology, 21(3), 274-286. https://doi.org/10.1038/s41590-020-0593-9