Upregulation of IFN-stimulated genes persists beyond the transitory broad immunologic changes of acute HIV-1 infection

Romel D Mackelprang; Abdelali Filali-Mouhim; Brian Richardson; Francois Lefebvre; Elly Katabira; Allan Ronald; Glenda Gray; Kristen W Cohen; Nichole R Klatt; Tiffany Pecor; Connie Celum; M Juliana McElrath; Sean M Hughes; Florian Hladik; Mark J Cameron; Jairam R Lingappa; Partners in Prevention HSV/HIV Transmission Study; Partners PrEP Study Teams

doi:10.1016/j.isci.2023.106454

Upregulation of IFN-stimulated genes persists beyond the transitory broad immunologic changes of acute HIV-1 infection

iScience. 2023 Mar 21;26(4):106454. doi: 10.1016/j.isci.2023.106454. eCollection 2023 Apr 21.

Authors

Romel D Mackelprang^{1

2}, Abdelali Filali-Mouhim³, Brian Richardson⁴, Francois Lefebvre⁵, Elly Katabira⁶, Allan Ronald⁷, Glenda Gray⁸, Kristen W Cohen⁹, Nichole R Klatt¹⁰, Tiffany Pecor¹¹, Connie Celum^{2

12

13}, M Juliana McElrath⁹, Sean M Hughes¹, Florian Hladik^{1

9

13}, Mark J Cameron⁴, Jairam R Lingappa^{2

13

14}; Partners in Prevention HSV/HIV Transmission Study; Partners PrEP Study Teams

Affiliations

¹ Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
² Department of Global Health, University of Washington, Seattle, WA, USA.
³ University of Montreal Hospital Research Center, Laval, QC, Canada.
⁴ Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁵ Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada.
⁶ Infectious Disease Institute, Makerere University, Kampala, Uganda.
⁷ Canada Departments of Medical Microbiology and Internal Medicine, University of Manitoba, Winnipeg, MB, USA.
⁸ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
⁹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹⁰ Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA.
¹¹ Washington National Primate Research Center, Seattle, WA, USA.
¹² Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹³ Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Department of Pediatrics, University of Washington, Seattle, WA, USA.

Abstract

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.

Keywords: Immunology; Molecular physiology; Virology.

Grants and funding

R01 AI134293/AI/NIAID NIH HHS/United States