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HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) leads to a chronic, incurable infection that causes immune activation, resulting in chronic inflammation in people with HIV-1 (PWH) despite virologic suppression on antiretroviral therapy (ART). The mechanisms underlying this chronic inflammation are multifactorial; literature supports the role of lymphoid structures as reservoirs for viral latency and immune activation. The cell type-specific transcriptomic changes induced by HIV-1 infection in lymphoid tissue have not been analyzed. Human tonsil explants from four donors were infected with HIV-1 ex vivo. Single-cell RNA sequencing (scRNA-seq) was performed to evaluate the represented cell types and the impact of infection, differential gene expression, and inflammatory signaling pathways. Infected CD4+ T cells exhibited increased respiratory electron transport pathway genes, activating oxidative phosphorylation. Additionally, macrophages exposed to the virus but uninfected demonstrated increased NLRP3 inflammasome pathway genes, activating the NLRP3 inflammasome and stimulating proinflammatory signaling pathways and pyroptotic cell death. These observations support important mechanistic understanding to drive the development of therapeutic strategies to eradicate disease in PWH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232477 | GEO | 2023/05/19

REPOSITORIES: GEO

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model

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