IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART
Abstract:
Cellular metabolism regulates HIV/SIV replication and reservoir establishment, yet how infection and antiretroviral therapy initiation (ARTi) shape the metabolism of CD4⁺ Tcells-main HIV target- in vivo remains poorly defined. Using the SIVmac239 macaque model, we integrated single-cell metabolic profiling (MIST), transcriptomics, lipidomics, genome-scale metabolic modeling, and functional assays to characterize their metabolic remodeling. At peak viremia, CD4⁺ T cells exhibited a marked shutdown of de novo fatty-acid (FA) synthesis, reflected by acetyl-CoA carboxylase-1 (ACC1) downregulation, inhibition of lipid-anabolic reactions, and depletion of membrane phospholipids. This metabolic state was driven by strong type I interferon (IFN-I) responses, and IFN-I exposure was sufficient to suppress ACC1 in vitro . Pharmacologic inhibition of FA synthesis independently enhanced Tcell activation and reduced HIV replication, indicating direct antiviral and immunomodulatory effects. Following ARTi, most metabolic pathways were broadly suppressed, whereas mitochondrial oxidative phosphorylation (OXPHOS) remained elevated. Together, these findings identify IFN-driven FA synthesis shutdown and persistent OXPHOS as defining metabolic features of early HIV/SIV infection and treatment initiation, highlighting these pathways as potential targets to limit viral replication and reservoir formation.
Insights
HIV/SIV infection alters CD4+ T cell metabolism, shutting down fatty-acid synthesis via interferon responses. Antiretroviral therapy initiation broadly suppresses metabolism, but mitochondrial function persists, offering potential therapeutic targets.
Area of Science:
- Immunology
- Virology
- Metabolomics
Background:
- Cellular metabolism critically influences HIV/SIV replication and the establishment of viral reservoirs.
- The metabolic reprogramming of CD4+ T cells during HIV/SIV infection and upon antiretroviral therapy initiation (ARTi) in vivo is not well understood.
- CD4+ T cells are the primary cellular targets for HIV infection.
Purpose of the Study:
- To comprehensively characterize the metabolic remodeling of CD4+ T cells during SIV infection and ARTi.
- To investigate the role of type I interferon (IFN-I) responses in metabolic alterations.
- To explore the potential of targeting metabolic pathways for antiviral and immunomodulatory strategies.
Main Methods:
- Utilized the SIVmac239 macaque model for in vivo studies.
- Integrated multi-omics approaches: single-cell metabolic profiling (MIST), transcriptomics, and lipidomics.
- Employed genome-scale metabolic modeling and functional assays to analyze metabolic pathways.
Main Results:
- At peak viremia, CD4+ T cells showed suppressed de novo fatty-acid (FA) synthesis, indicated by ACC1 downregulation and reduced membrane phospholipid content.
- Type I interferon (IFN-I) responses were identified as the driver of FA synthesis shutdown, with IFN-I sufficient to suppress ACC1 in vitro.
- Pharmacologic inhibition of FA synthesis demonstrated direct antiviral effects by reducing HIV replication and enhancing T cell activation.
- Following ARTi, metabolic pathways were generally suppressed, but mitochondrial oxidative phosphorylation (OXPHOS) remained elevated.
Conclusions:
- IFN-driven shutdown of FA synthesis is a key metabolic feature of early HIV/SIV infection.
- Persistent elevated OXPHOS post-ARTi characterizes the metabolic state during treatment initiation.
- Targeting FA synthesis and OXPHOS pathways may offer novel strategies to limit viral replication and reservoir formation.
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