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

Introduction: 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 (PLWHIV). Methods: We enrolled a cross-sectional cohort study of PLWHIV on stable antiretroviral therapy (cART; n=211) and HIV uninfected controls (n=56). We performed peripheral blood mononuclear cell stimulation to assess ex vivo cytokine production and transcriptomics of monocytes and T lymphocytes upon bacterial, fungal and viral stimulation. We used a linear regression model with age, sex, BMI and seasonality as covariates to compare both cohorts. All p-values are FDR-corrected. Results: PLWHIV exhibited an exacerbated pro-inflammatory profile in monocyte-derived cytokines, but not of lymphocyte-derived cytokines. Especially the interleukin (IL)-1β response to imiquimod (TLR7), lipopolysaccharide (LPS) and Mycobacterium tuberculosis was increased and correlated with plasma concentrations of high-sensitive C-reactive protein and soluble CD14. The increase in monocyte responsiveness remained stable over-time in subsequent blood sampling. Transcriptome analyses confirmed priming of the monocyte IL1β 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. Conclusions: Monocytes of PLWHIV on stable cART exhibit a sustained pro-inflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLWHIV is likely to play a role in the long-term HIV complications and forms an attractive therapeutic target for inflammation-related comorbidities. Analysis of the behaviour of monocytes (as a compartment of innate immune system) from healthy volunteers and HIV positive donors in RPMI cell culture. **Submitter declares that donor consent does not allow deposit of raw data files**