HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells
Lifshitz, Lawrence M.
McCauley, Sean M.
Derr, Alan G.
Greenough, Thomas C.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Biochemistry and Molecular Pharmacology
Department of Medicine
Program in Bioinformatics and Integrative Biology
Program in Molecular Medicine
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Genetics and Genomics
Immunology and Infectious Disease
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AbstractHuman 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/25874
Full author list omitted for brevity. For the full list of authors, see article.