Chronic immune activation during HIV-1 infection contributes to morbidity and mortality in people living with HIV. To elucidate the underlying biological pathways, we evaluated whole blood gene expression trajectories from before, through acute, and into chronic HIV-1 infection. Interferon-stimulated genes, including MX1, IFI27 and ISG15, were upregulated during acute infection, remained elevated into chronic infection, and were strongly correlated with plasma HIV-1 RNA as well as TNF-α and CXCL10 cytokine levels. In contrast, genes involved in cellular immune responses, such as CD8A, were upregulated during acute infection before reaching a peak and returning to near pre-infection levels in chronic infection. Our results indicate that chronic immune activation during HIV-1 infection is characterized by persistent elevation of a narrow set of interferon-stimulated genes and innate cytokines. These findings raise the prospect of devising a targeted intervention to restore healthy immune homeostasis in people living with HIV-1.
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The Partners in Prevention HSV/HIV Transmission Study Team (sites permitting host genomic studies): University of Washington Coordinating Center and Central Laboratories, Seattle: Connie Celum (principal investigator), Anna Wald (protocol cochair), Jairam Lingappa (medical director), Jared M. Baeten, Mary Campbell, Lawrence Corey, Robert W. Coombs, James P. Hughes, Amalia Magaret, M. Juliana McElrath, Rhoda Morrow, and James I. Mullins. Study sites and site principal investigators: in Cape Town, South Africa, David Coetzee (University of Cape Town); in Eldoret, Kenya, Kenneth Fife and Edwin Were (Moi University and Indiana University); in Gaborone, Botswana, Max Essex and Joseph Makhema (Botswana Harvard Partnership); in Kampala, Uganda, Elly Katabira and Allan Ronald (Infectious Disease Institute, Makerere University; in Kisumu, Kenya, Elizabeth Bukusi and Craig Cohen (Kenya Medical Research Institute and University of California–San Francisco); in Moshi, Tanzania, Saidi Kapiga and Rachel Manongi (Kilimanjaro Christian Medical College and Harvard University); in Nairobi, Kenya, Carey Farquhar, Grace John-Stewart, and James Kiarie (University of Nairobi and University of Washington); in Orange Farm, South Africa, Sinead Delany-Moretlwe and Helen Rees (Reproductive Health Research Unit and University of the Witwatersrand); in Soweto, South Africa, Guy deBruyn, Glenda Gray, and James McIntyre (Perinatal HIV Research Unit, University of the Witwatersrand); in Thika, Kenya, Nelly Rwamba Mugo (University of Nairobi and University of Washington). We also thank Case Western Reserve University's Applied Functional Genomics Core for their assistance in the microarray assays. Funding: Funding for this work was through the Bill and Melinda Gates Foundation grants #26469 and #41185, and NIH/NIAID grants R21 A1087427, P30 AI036219 and R01 AI134293. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conceptualization: R.D.M. M.J.C. F.H. and J.R.L.; Methodology: R.D.M. A.F-M. F.L. and B.R.; Formal Analysis: R.D.M. A.F. and F.L.; Investigation: R.D.M. M.J.C. E.K. A.R. G.G. K.W.C. N.R.K. T.P. C.C. M.J.M. and J.R.L.; Investigation: M.J.C. K.W.C. N.R.K. T.P. and J.R.L.; Resources: E.K. A.R. G.G. C.C. M.J.M. and J.R.L.; Data curation: R.D.M. A.F. B.R. and F.L.; Writing – Original Draft: R.D.M. M.J.C. A.F. and J.R.L.; Writing – Review and Editing: B.R. F.L. E.K. A.R. G.G. K.W.C. N.R.K. T.P. C.C. M.J.M. S.M.H. F.H. and J.R.L.; Visualization: R.D.M. and A.F.; Supervision: M.J.C. and J.R.L.; Project Administration: R.D.M. M.J.C. and J.R.L.; Funding Acquisition, R.D.M. M.J.C. and J.R.L. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Funding: Funding for this work was through the Bill and Melinda Gates Foundation grants #26469 and #41185 , and NIH / NIAID grants R21 A1087427 , P30 AI036219 and R01 AI134293 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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- Molecular physiology
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