HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells
Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology; Department of Medicine; Department of Biochemistry and Molecular Pharmacology; Garber Lab; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Genetics and Genomics | Immunology and Infectious Disease | Microbiology | Viruses
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.
Immunology, Infectious diseases, Microbiology, Molecular biology
DOI of Published Version
Wang Y, Lifshitz L, Gellatly K, Vinton CL, Busman-Sahay K, McCauley S, Vangala P, Kim K, Derr A, Jaiswal S, Kucukural A, McDonel P, Hunt PW, Greenough T, Houghton J, Somsouk M, Estes JD, Brenchley JM, Garber M, Deeks SG, Luban J. HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells. Nat Immunol. 2020 Mar;21(3):274-286. doi: 10.1038/s41590-020-0593-9. Epub 2020 Feb 17. PMID: 32066947; PMCID: PMC7044076. Link to article on publisher's site
Wang Y, Lifshitz LM, K, McCauley SM, Vangala P, Kim K, Derr AG, Jaiswal S, Kucukural A, McDonel P, Greenough TC, Houghton J, Garber M, Luban J. (2020). HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells. Program in Bioinformatics and Integrative Biology Publications. https://doi.org/10.1038/s41590-020-0593-9. Retrieved from https://escholarship.umassmed.edu/bioinformatics_pubs/167