ArticleRetrovirology2011
Nef-mediated enhancement of cellular activation and human immunodeficiency virus type 1 replication in primary T cells is dependent on association with p21-activated kinase 2.
Article in Retrovirology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question!Current issues in molecular biology · 2024Review
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- HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission.Cell host & microbe · 2019Article
- The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4Retrovirology · 2018Article
- Down-modulation of primate lentiviral receptors by Nef proteins of simian immunodeficiency virus (SIV) of chimpanzees (SIVcpz) and related SIVs: implication for the evolutionary event at the emergence of SIVcpz.The Journal of general virology · 2015Article
- Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation.The Journal of general virology · 2015Article
- Review
- Identification of core T cell network based on immunome interactome.BMC systems biology · 2014Article
- In vivo analysis of highly conserved Nef activities in HIV-1 replication and pathogenesis.Retrovirology · 2013Article
- HIV-1 Nef and T-cell activation: a history of contradictions.Future virology · 2013Article
- Impact of cellular autophagy on viruses: Insights from hepatitis B virus and human retroviruses.Journal of biomedical science · 2012Review
- Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation.Retrovirology · 2012Article
- Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development.The Journal of general virology · 2012Article
- Overlapping effector interfaces define the multiple functions of the HIV-1 Nef polyproline helix.Retrovirology · 2012Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe HIV-1 accessory protein Nef is an important determinant of lentiviral pathogenicity that contributes to disease progression by enhancing viral replication and other poorly understood mechanisms. Nef mediates diverse functions including downmodulation of cell surface CD4 and MHC Class I, enhancement of viral infectivity, and enhancement of T cell activation. Nef interacts with a multiprotein signaling complex that includes Src family kinases, Vav1, CDC42, and activated PAK2 (p21-activated kinase 2). Although previous studies have attempted to identify a biological role for the Nef-PAK2 signaling complex, the importance of this complex and its constituent proteins in Nef function remains unclear.
resultsHere, we show that Nef mutants defective for PAK2-association, but functional for CD4 and MHC Class I downmodulation and infectivity enhancement, are also defective for the ability to enhance viral replication in primary T cells that are infected and subsequently activated by sub-maximal stimuli (1 μg/ml PHA-P). In contrast, these Nef mutants had little or no effect on HIV-1 replication in T cells activated by stronger stimuli (2 μg/ml PHA-P or anti-CD3/CD28-coated beads). Viruses bearing wild-type Nefs, but not Nef mutants defective for PAK2 association, enhanced NFAT and IL2 receptor promoter activity in Jurkat cells. Moreover, expression of wild-type Nefs, but not mutant Nefs defective for PAK2 association, was sufficient to enhance responsiveness of primary CD4 and CD8 T cells to activating stimuli in Nef-expressing and bystander cells. siRNA knockdown of PAK2 in Jurkat cells reduced NFAT activation induced by anti-CD3/CD28 stimulation both in the presence and absence of Nef, and expression of a PAK2 dominant mutant inhibited Nef-mediated enhancement of CD25 expression.
conclusionNef-mediated enhancement of cellular activation and viral replication in primary T cells is dependent on PAK2 and on the strength of the activating stimuli, and correlates with the ability of Nef to associate with PAK2. PAK2 is likely to play a role in Nef-mediated enhancement of viral replication and immune activation in vivo.
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Registered trials
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