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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160184 | GEO | 2021/05/19

REPOSITORIES: GEO

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Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.

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

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