Chronic HIV infection induces transcriptional and functional reprogramming of innate immune cells

• Published in: JCI insight 2021-04, Vol.6 (7)
• Main Authors: van der Heijden, Wouter A, Van de Wijer, Lisa, Keramati, Farid, Trypsteen, Wim, Rutsaert, Sofie, Horst, Rob Ter, Jaeger, Martin, Koenen, Hans Jpm, Stunnenberg, Hendrik G, Joosten, Irma, Verweij, Paul E, van Lunzen, Jan, Dinarello, Charles A, Joosten, Leo Ab, Vandekerckhove, Linos, Netea, Mihai G, van der Ven, André Jam, de Mast, Quirijn
• Format: Article
• Language: English
• Subjects: Adult; AIDS/HIV; Anti-HIV Agents - therapeutic use; beta-Glucans - metabolism; Case-Control Studies; Chronic Disease; Cytokines - genetics; Cytokines - immunology; Female; Gene Expression; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - immunology; Humans; Immunity, Innate - genetics; Immunology; Inflammation - blood; Inflammation - immunology; Inflammation - virology; Interleukin-1beta - blood; Interleukin-1beta - genetics; Lipopolysaccharides - pharmacology; Male; Middle Aged; Monocytes - immunology; Monocytes - virology; Neutrophils - drug effects; Neutrophils - immunology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.145928

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS-related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T cells upon bacterial, fungal, and viral stimulation. PLHIV exhibited an exacerbated proinflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS, and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of high-sensitivity C-reactive protein and soluble CD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after more than 1 year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte-trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibited a sustained proinflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.