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

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

PROVIDER: PRJNA594204 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10606400.fastq.gz	Fastqsanger.gz
	SRR10606500.fastq.gz	Fastqsanger.gz
	SRR10606600.fastq.gz	Fastqsanger.gz
	SRR10606401.fastq.gz	Fastqsanger.gz
	SRR10606501.fastq.gz	Fastqsanger.gz

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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

Nef-Mediated CD3-TCR Downmodulation Dampens Acute Inflammation and Promotes SIV Immune Evasion.

Project description:The inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-mediated immune activation and pathogenicity remains 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-TCR does not impair viral replication during acute infection but is associated with increased immune activation and antiviral gene expression. Subsequent early reversion in three of six animals suggests strong selective pressure for this Nef function and is associated with high viral loads and progression to simian AIDS. In the absence of reversions, however, viral replication and the clinical course of infection are attenuated. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to simian immunodeficiency virus (SIV) infection and seems critical for efficient viral immune evasion.

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Gene expression in the blood of Live Attenuated Rev-Independent Nef¯SIV infected Rhesus macaques during acute infection

Project description:Rhesus macaques (RMs) inoculated with live-attenuated Rev-Independent Nef¯ simian immunodeficiency virus (Rev-Ind Nef¯SIV) as adults or neonates controlled viremia to undetectable levels and showed no signs of immunodeficiency over 6-8 years of follow-up. We tested the capacity of this live-attenuated virus to protect RMs against pathogenic, heterologous SIVsmE660 challenges

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Nef transfection of Jurkat T cells

Project description:Jurkat T cell line was transfected with SIV Nef controlled by an unducible promoter system. Nef was induced by addition of 10 micromolar pronasterone A and gene expression values were determined after 24 hrs. Control Jurkat cells were untransfected and treated with 10 micromolar pronasterone A and gene expressio values were determined after 24 hrs. Keywords: SIV Nef, Jurkat, pronasterone A

2006-07-25 | GSE4785 | GEO

HIV Nef transfected HEK293T cell culture and HIV mock transfected HEK293T cell culture [miRNA]

Project description:Purpose: Comparison of RNA-sequencing datasets obtained from exosomes of Nef-transfected and Mock-transfected HEK293T cells Methods: Assessment of RNA content of exosomes produced by Nef-transfected HEK293T cells and and Mock-transfected HEK293T cells Results: Differences in a set of microRNAs Conclusions: Nef-transfection induces changes in the microRNA content of exosomes

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HIV Nef transfected HEK293T cell culture and HIV mock transfected HEK293T cell culture [mRNA]

Project description:Purpose: Comparison of RNA-sequencing datasets obtained from exosomes of Nef-transfected and Mock-transfected HEK293T cells. Methods: Assessment of RNA content of exosomes produced by Nef-transfected HEK293T cells and and Mock-transfected HEK293T cells. Results: Differences in a set of mRNAs. Conclusions: Nef-transfection might induces changes in the mRNA content of exosomes.

2018-11-18 | GSE122655 | GEO

Characterization of mammalian NEF-sp as a testis-specific nuclear 3′→5′ exoribonuclease

Project description:Ribonucleases catalyse maturation of functional RNAs or mediate degradation of cellular transcripts, activities that are critical for gene expression control. Here we identify a previously uncharacterized mammalian nuclease family member NEF-sp (LOC81691) as a testis-specific factor. Recombinant human NEF-sp demonstrates a divalent metal ion-dependent 3′→5′ exoribonuclease activity. This activity is specific to single-stranded RNA substrates and is independent of their length. Presence of a 2′-O-methyl modification at the 3′ end of the RNA substrate is inhibitory. Ectopically-expressed NEF-sp localizes to the nucleolar/nuclear compartment in human cell cultures and this is dependent on an N-terminal nuclear localization signal. Finally, mice lacking NEF-sp are viable and display normal fertility, likely indicating overlapping functions with other nucleases. Taken together, our study provides the first biochemical and genetic exploration of the role of the NEF-sp exoribonuclease in the mammalian genome.

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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.

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HIV-1 TAT SUPPRESSES THE TCR/CD3 MACHINERY IN HUMAN CD4+ T CELLS

Project description:Our previous work demonstrated that HIV-1 infection progressively reduces TCR/CD3 expression due to a defect in CD3g gene transcripts. We further found that knocking down expression of the viral tat and/or nef genes was correlated with CD3g transcript and TCR/CD3 surface receptor levels on HIV-1 infected cells. This study was undertaken to investigate the direct effect of HIV-1 Tat expression on the TCR/CD3 machinery. Progressive downregulation from TCR/CD3hi to TCR/CD3lo to TCR/CD3? was observed on Tat expressing cells in a manner that emulated HIV-1 infection, with a lack of CD3g transcripts again responsible for the defect. When Tat cell cultures containing a mixture of TCR/CD3 surface densities were separated into TCR/CD3hi and TCR/CD3lo/? populations, they quickly reverted to a mixed CD3 phenotype. Thus, the progression TCR/CD3hi to TCR/CD3lo to TCR/CD3? is an active, reversible process with receptor levels fluctuating in response to intracellular dynamics. Examination of tat mutants found that the regions involved in Tat-mediated transactivation and TAR binding are required for TCR/CD3 downregulation while the lysine at position 28 and Tat exon 2 are dispensable. Global gene expression, assessed in association with TCR/CD3 downregulation in HIV-1 infected and Tat expressing cells, detected broad suppression of TCR/CD3 signaling, co-stimulation and negative regulatory genes along with target transcription factors, ligands and receptors. A significant subset of the genes altered in HIV-1 infected cells was specifically targeted by Tat in association with TCR/CD3 loss. Our finding that Tat negatively regulates many facets of the TCR/CD3 machinery has important implications for disease pathogenesis. This SuperSeries is composed of the SubSeries listed below.

2015-12-31 | GSE32626 | GEO

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

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2024-01-26 | PXD041028 | Pride

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