A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size.

Autor: Dwivedi AK; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Gornalusse GG; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America., Siegel DA; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Barbehenn A; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Thanh C; Department of Medicine, Division of Experimental Medicine, University of California San Francisco, California, United States of America., Hoh R; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Hobbs KS; Department of Medicine, Division of Experimental Medicine, University of California San Francisco, California, United States of America., Pan T; Department of Medicine, Division of Experimental Medicine, University of California San Francisco, California, United States of America., Gibson EA; Department of Medicine, Division of Experimental Medicine, University of California San Francisco, California, United States of America., Martin J; Department of Biostatistics & Epidemiology, University of California San Francisco, California, United States of America., Hecht F; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Pilcher C; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Milush J; Department of Medicine, Division of Experimental Medicine, University of California San Francisco, California, United States of America., Busch MP; Vitalant Blood Bank, San Francisco, California, United States of America., Stone M; Vitalant Blood Bank, San Francisco, California, United States of America., Huang ML; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, United States of America., Reppetti J; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America.; Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO- Houssay), Buenos Aires, Argentina., Vo PM; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America., Levy CN; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America., Roychoudhury P; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, United States of America., Jerome KR; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, United States of America., Hladik F; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America.; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, United States of America., Henrich TJ; Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, United States of America., Deeks SG; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America., Lee SA; Department of Medicine, Division of HIV, Infectious Diseases & Global Medicine, University of California, San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Nov 29; Vol. 19 (11), pp. e1011114. Date of Electronic Publication: 2023 Nov 29 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011114
Abstrakt: The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Dwivedi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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