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ScRNA-seq of Mycobacterium tuberculosis-specific CD4 T cells from Kenyan women with and wihtout HIV and before and after ART initiation following stimulation with Mtb WCL

ABSTRACT: To understand how HIV and timing of ART initiation affect the transcriptional profile of Mtb-specific CD4 T cells, we performed 10X single-cell RNA sequencing comparing Mtb-specific CD4 T cell transcriptomes from people without HIV, people with HIV prior to ART, and people with HIV after ART from the Mombasa Cohort in Mombasa, Kenya. PBMCs were stimulated overnight with Mycobacterium tuberculosis whole cell lysate and CD40L+CD69+ Mtb-specifc CD4 T cells were sorted for sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299662 | GEO | 2025/07/10

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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ScRNA-seq of Mycobacterium tuberculosis-specific CD4 T cells from Kenyan women with and wihtout HIV and before and after ART initiation following stimulation with Mtb WCL

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