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HIV-1 Nef programs long-lasting innate immune memory in hematopoietic stem and progenitor cells in a mouse model

ABSTRACT: The HIV infection is accompanied by chronic inflammation and inflammation-related co-morbidities, even when viral replication is effectively supressed by therapy. It is often assumed that a complete cure would resolve this inflammation; however its origin and mechanisms may be more complex and not entirely dependent on the continuous presence of the virus. To investigate whether inflammatory programming can be imprinted in hematopoietic cells, we treated mice with extracellular vesicles containing the HIV protein Nef (exNef), a major viral pathogenic and inflammatory factor. Using a multi-omics approach, we found that haematopoietic cells exposed to exNef displayed epigenetic modifications and reprogramming of energy and lipid metabolism pathways characteristic of trained innate immunity (TRIM).

ORGANISM(S): Mus musculus

PROVIDER: GSE320286 | GEO | 2026/04/16

REPOSITORIES: GEO

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Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells [ATAC-Seq]

Project description:A possible explanation for chronic inflammation in HIV-infected individuals treated with anti-retroviral therapy is hyperreactivity of myeloid cells due to a phenomenon called ‘trained immunity’. Here, we demonstrate that human monocyte-derived macrophages originating from monocytes initially treated with extracellular vesicles containing HIV-1 protein Nef (exNef), but differentiating in the absence of exNef, released increased levels of pro-inflammatory cytokines after lipopolysaccharide stimulation. This effect was associated with epigenetic changes related to inflammation and cholesterol metabolism pathways, upregulation of the lipid rafts, and was blocked by methyl-beta-cyclodextrin, statin, and by an inhibitor of the lipid raft-associated receptor IGF1R. Bone marrow-derived macrophages from exNef-injected mice, as well as from mice transplanted with bone marrow from exNef-injected animals, produced elevated levels of TNFalpha upon stimulation. These phenomena are consistent with exNef-induced trained immunity that may contribute to persistent inflammation and associated co-morbidities in HIV-infected individuals with undetectable HIV load.

2022-10-09 | GSE214958 | GEO

Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells [RNA-Seq]

2022-10-09 | GSE214957 | GEO

Nef-mediated downmodulation of CD3 dampens immune activation and is critical for maintenance of high virus loads in SIV-infected macaques

Project description:The inability of Nef to downmodulate the T cell receptor CD3 distinguishes HIV-1 from most other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in viral immune evasion and pathogenicity remained speculative. Here, we selectively disrupted this Nef activity in SIVmac239 and analyzed the consequences for the virological, immunological and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3 did not affect viral replication during acute infection but was associated with increased immune activation and antiviral gene expression. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to SIV infection and is critical for viral immune evasion.

2020-03-09 | GSE141626 | GEO

Gene expression profiling of CD4+ T cell line due to presence of Nef during HIV-1 infection.

Project description:We have utilized microarray technology to compare gene expression profile in presence or absence of Nef during HIV-1 infection in T cell-line. We found several genes significantly differentially regulated due to ∆nef HIV-1 infection and WT HIV-1 infection when compared to Uninfected cells and also several genes significantly dergulated due to WT HIV-1 infection as compared to ∆nef HIV-1 infection. We redistributed genes belonging to several gene ontology into broad categories like “signaling”, “apoptosis”, “transcription” and “lipid metabolism”. We selected some lipid metabolism genes to validate the Nef directed differential expression using quantitative real-time RT-PCR. Thus the present work highlights the importance of Nef directed differential gene expression in milieu of other viral proteins present during infection.

2016-12-06 | GSE76793 | GEO

Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model.

Project description:Loss of function mutations in the human immunodeficiency virus (HIV)-negative factor (Nef) gene are associated with reduced viremia, robust T cell immune response, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. Additionally, in vitro studies have shown that mutations in Nef's dimerization interface may play a significant role in modulating viral replication and impairing host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodent models with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. We recently developed the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model, which carries human immune cells, as well as primary and secondary lymphoid tissues that facilitate anti-viral immune responses. Here, we employed the BLTS-humanized mouse model to demonstrate that preventing Nef dimerization abrogates HIV viremia and the associated induction of immune dysregulation (immune activation and exhaustion). This suggests that Nef dimerization may be a therapeutic target for future HIV cure strategies, which can be explored in humanized mouse models.

2021-03-10 | GSE165387 | GEO

HIV-1 Nef Reprograms Neuronal Lipid Rafts to Drive Neuroinflammation and Neurodegeneration in HIV-associated Neurocognitive Impairment

Project description:HIV-associated neurological disorders (HAND) remain a common co-morbidity of HIV infection. HIV protein Nef has been shown to increase the abundance of neuronal lipid rafts - cholesterol- and sphingolipid-rich membrane microdomains implicated in neurodegeneration and neuroinflammation. Here, we investigated how Nef-containing extracellular vesicles (exNef) secreted by glial cells influence the structural and functional properties of neuronal lipid rafts and contribute to HAND pathogenesis. Lipidomics analysis of isolated neuronal lipid raft fractions revealed minimal impact of exNef on the raft lipid composition; physico-chemical properties of the lipid rafts were also unaffected. In contrast, proteomic analysis revealed that among raft proteins with increased abundance following exNef exposure, ～25% were implicated in neurological disease pathways. Notably, this protein signature showed strong concordance with transcriptomic profiles from single-nucleus RNA sequencing (snRNA-seq) of brain from HIV-infected individuals. Targeted protein analysis unveiled that exNef promotes the redistribution of several neurodegenerative and inflammatory proteins to the lipid rafts, resulting in increased inflammation and apoptosis alongside reduced neuronal excitability. Pharmacological disruption of raft elevation with the lipid raft antagonist Oxy210 reversed exNef-induced raft expansion and abrogated these structural and functional alterations. In summary, exNef reorganize the neuronal lipid raft proteome, enhancing the activity of neurodegenerative and inflammatory mediators, thereby contributing to HAND pathogenesis.

2026-03-23 | PXD065713 | Pride

HIV-1 Nef changes the proteome of T cells extracellular vesicles

Project description:Extracellular vesicles (EVs) are biomolecule carriers for intercellular communication in health and disease. Nef is a human immunodeficiency virus (HIV) virulence factor that is released from cells within EVs and is present in plasma EVs of HIV-1 infected individuals. We performed a quantitative proteomic analysis to fully characterize the Nef-induced changes in protein composition of T cell-derived EVs and identify novel host targets of HIV. Several proteins with well-described roles in infection or not previously associated with HIV pathogenesis were specifically modulated by Nef in EVs. Among the downregulated proteins are the interferon-induced transmembrane 1, 2 and 3 proteins (IFITM1-3), broad-spectrum antiviral factors known to be cell-to-cell transferable by EVs. Our data establish Nef as a modulator of EVs' global protein content and as an HIV factor that antagonizes IFITMs.

2024-01-26 | PXD041028 | Pride

HIV-1 Nef protein promotes the proliferation of lymphoma cells by activating the NF-κB pathway

Project description:The prevalence of lymphoma in people living with HIV is remarkably higher compared to that of the general population, and the overall survival is markedly lower compared to that of lymphoma patients without HIV. In this study, we have demonstrated that the HIV-encoded negative regulatory factor (Nef) directly promotes lymphoma cell proliferation. We have also observed that Nef significantly upregulates key genes and proteins of the NF-κB signaling pathway, thereby promoting growth of lymphoma cells. These observations underscore the increasingly recognized role of HIV-encoded proteins as oncogenic drivers, providing fundamental mechanistic insights into the manner in which viral factors exploit host signaling networks to fuel lymphomagenesis.

2025-12-19 | PXD072199 |

Probe to gene expressions in HIV infected CD4 T cells in the presence of CDK, caspase inhibitors and Nef

Project description:HIV-1 infection selectively alters gene expressions of CD4 T cells. To understand the effects of HIV to the expressions of CDK and caspase pathway genes in the presence and absence of Nef, we infected CD8-depleted PBMC from healthy donors with HIV-1 BAL in the presence of BB-94, PD-0332991, QVD-OPH or DMSO control, or with Nef-sufficient, Nef-deficient Vpu-sufficient, Vpu-deficient NL4-3 strain of HIV-1. On day 6 of infection, cells were enriched for CD4 T cells for gene expression profile analyses by RNA sequencing. We then performed gene expression profiling analysis using data obtained from RNA-seq of 16 different treated CD4 T cells.

2023-11-23 | GSE218175 | GEO

Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef

Project description:Critical cell surface immunoreceptors downregulated by HIV have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T-cell surface, we took a distinct, systems-level, quantitative proteomic approach. HIV downregulated >100 plasma membrane proteins, many without characterised roles in the immune system. An exclusive group of host factors were targeted by the viral accessory proteins Vpu or Nef, including the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focussed on SNAT1, a novel, ß- TrCP-dependent Vpu substrate. Antagonism of SNAT1 emerges in Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T-cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T- cell mitogenesis. Downregulation of SNAT1 therefore defines a novel paradigm of viral interference with immunometabolism.

2015-11-09 | PXD002934 | Pride

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