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HIV silencing and cell survival signatures in infected T cell reservoirs.

ABSTRACT: Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure^1-3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA⁺ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA⁺ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA⁺ cells, positive regulators of HIV transcription that were lower in HIV-DNA⁺ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies.

SUBMITTER: Clark IC

PROVIDER: S-EPMC9908556 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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HIV silencing and cell survival signatures in infected T cell reservoirs.

Clark Iain C IC Mudvari Prakriti P Thaploo Shravan S Smith Samuel S Abu-Laban Mohammad M Hamouda Mehdi M Theberge Marc M Shah Sakshi S Ko Sung Hee SH Pérez Liliana L Bunis Daniel G DG Lee James S JS Kilam Divya D Zakaria Saami S Choi Sally S Darko Samuel S Henry Amy R AR Wheeler Michael A MA Hoh Rebecca R Butrus Salwan S Deeks Steven G SG Quintana Francisco J FJ Douek Daniel C DC Abate Adam R AR Boritz Eli A EA

Nature 20230104 7947

Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure<sup>1-3</sup>, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA<s ...[more]

PMID: 36599978

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Project description:The oral epithelium, the most abundant structural tissue lining the oral mucosa, is an important line of defense against infectious microorganisms. HIV infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid viral, bacterial and fungal infections in the oral cavity. To provide an assessment of the molecular alterations of oral epithelia potentially associated with susceptibility to comorbid infections in such subjects, we performed various proteomic studies on over twenty HIV infected and healthy subjects. In a discovery phase two Dimensional Difference Gel Electrophoresis (2-D DIGE) analyses of human oral gingival epithelial cell (HOEC) lysates were carried out; this identified 61 differentially expressed proteins between HIV-infected on HAART subjects and healthy controls. Down regulated proteins in HIV-infected subjects include proteins associated with maintenance of protein folding and pro- and anti-inflammatory responses (e.g., heat-shock proteins, Cryab, Calr, IL-1RA, and Galectin-3-binding protein) as well as proteins involved in redox homeostasis and detoxification (e.g., Gstp1, Prdx1, and Ero1). Up regulated proteins include: protein disulfide isomerases, proteins whose expression is negatively regulated by Hsp90 (e.g., Ndrg1), and proteins that maintain cellular integrity (e.g., Vimentin). In a verification phase, proteins identified in the protein profiling experiments and those inferred from Ingenuity Pathway Analysis were analyzed using Western blotting analysis on separate HOEC lysate samples, confirming many of the discovery findings. Additionally in HIV-infected patient samples Heat Shock Factor 1 is down regulated, which explains the reduced heat shock responses, while activation of the MAPK signal transduction cascade is observed. Overall, HAART therapy provides an incomplete immune recovery of the oral epithelial cells of the oral cavity for HIV-infected subjects, and the toxic side effects of HAART and/or HIV chronicity silence expression of multiple proteins that in healthy subjects function to provide robust innate immune responses and combat cellular stress.

Project description:ObjectiveNumerous studies have reported on the pathogenesis of poor immune reconstitution (PIR) after antiretroviral treatment in human immunodeficiency virus (HIV) patients. However, fewer studies focused on both immune-related genes (IRGs) and immune cells, and the correlation between IRGs and immune cells was evaluated via bioinformatics analyses.MethodsGene expression profiling of GSE143742 from the Gene Expression Omnibus (GEO) database was analyzed to get differentially expressed immune-related genes (DEIRGs). The enrichment analysis and protein-protein interaction (PPI) networks of DEIRGs were established. The relative fractions of 22 immune cell types were detected using the "CIBERSORT". The correlation analysis between DEIRGs and immune cells was constructed to discover the potential IRGs associated with immune cells. A logistic regression diagnostic model was built, and a receiver operating characteristic (ROC) curve was performed to evaluate the model's diagnostic efficacy. The CMap database was used to find molecules with therapeutic potential. RT-qPCR was used to verify the expression of the hub DEIRGs.ResultsWe identified eight types of significantly changed immune cells and five hub IRGs in INRs. The DEIRGs were mainly enriched in lymphocyte activation, receptor-ligand activity, and T cell receptor signaling pathway. The correlation analysis showed that the expression of TNF, CXCR4 and TFRC correlate with CD8 cells, resting mast cells, activated NK cells, and naïve CD4 cells in INRs. Meanwhile, TFRC and IL7R relate to activated NK cells and resting memory CD4 cells respectively in IRs. A diagnostic model was constructed using multiple logistic regression and nine small molecules were identified as possible drugs.ConclusionIn this study, we suggested that the process of PIR might be related to TNF, CXCR4, TFRC, CD48, and IL7R. And these IRGs play roles in regulating immune-competent cells. And our constructed diagnostic model has excellent effectiveness. Moreover, some small-molecule drugs are screened to alleviate PIR.

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HIV silencing and cell survival signatures in infected T cell reservoirs.

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HIV silencing and cell survival signatures in infected T cell reservoirs.

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