HIV-1 Nef control of cell signalling molecules: Multiple strategies to promote virus replication

  title={HIV-1 Nef control of cell signalling molecules: Multiple strategies to promote virus replication},
  author={Alison L. Greenway and Gavan Holloway and Dale A. McPhee and Phoebe Ellis and Alyssa M. Cornall and Michael Lidman},
  journal={Journal of Biosciences},
HIV-1 has at its disposal numerous proteins encoded by its genome which provide the required arsenal to establish and maintain infection in its host for a considerable number of years. One of the most important and enigmatic of these proteins is Nef. The Nef protein of HIV-1 plays a fundamental role in the virus life cycle. This small protein of approximately 27 kDa is required for maximal virus replication and disease progression. The mechanisms by which it is able to act as a positive factor… 
Implications of Nef: host cell interactions in viral persistence and progression to AIDS.
An overview on selected Nef interactions with host cell proteins is provided, and their possible relevance for viral spread and pathogenicity is discussed.
To explore the structure of the Nef:Tec-family kinase (TFK) complexes, a panel of bacterial expression constructs for the Itk and Btk regulatory region is created, and preliminary Surface Plasmon Resonance studies show that Myr-Nef binds membrane bilayers with low µM affinity in a Myr-dependent manner.
Potential roles of Nef and Vpu in HIV-1 latency
How antagonistic and synergistic functions of Nef and Vpu might affect HIV-1 latency is reviewed and whether these two accessory factors represent suitable targets to improve the ‘shock and kill’ cure strategy is discussed.
The results presented here advance the field of HIV research by furthering the understanding of the interaction between the HIV-1 Nef virulence factor and the Src kinase family, as well as validating this virus:host cell interaction as a rational target for anti-HIV drug discovery.
The immunoregulatory effects of HIV‐1 Nef on dendritic cells and the pathogenesis of AIDS
It is demonstrated that Nef subverts DC biology interfering with phenotypical, morphological, and functional DC developmental programs, thus representing a viral tool underlying AIDS pathogenesis and contributing to the understanding of Nef function, mechanism of action, and cellular partners.
HIV-1 Nef-Src Family Kinase Interaction: A Novel Target for the Inhibition of HIV-1 Pathogenesis
This dissertation project explored whether Src-family kinase (SFK) activation is a conserved property of nef alleles from a wide range of primary HIV-1 isolates and its sensitivity to selective pharmacological inhibitors, and demonstrated that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV- 1.
HIV-1 Nef Signaling in Intestinal Mucosa Epithelium Suggests the Existence of an Active Inter-kingdom Crosstalk Mediated by Exosomes
The effects of HIV-1 Nef protein on intestinal epithelium are discussed, the existence of an inter-kingdom communication process mediated by exosomes is proposed and the potential inter-Kingdom communication pathway between virus and humans is considered.
Bimolecular Fluorescence Complementation Reveals that HIV-1 Nef Oligomerization is Essential for CD4 Downregulation and Viral Replication
The studies presented in this dissertation advance the field of HIV research by furthering the understanding of the regulation of Nef-mediated downregulation of CD4 and enhancement of HIV replication as well as validating the Nef oligomerization interface as a potential target for anti-retroviral drug design.
Nef and cell signaling transduction: a possible involvement in the pathogenesis of human immunodeficiency virus-associated dementia
It is shown that HIV-1 Nef has an effect on the transcriptional levels of a cellular protein, anaplastic lymphoma kinase (ALK), that is preferentially expressed in the central and peripheral nervous system at late embryonic stages, which may indicate that, thanks to its ability to interfere with specific cellular pathways involved in BBB damage and in central nervous system (CNS) integrity, Nef could be one of the viral players implicated in HAD development.


HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell
It is shown that HIV-1 Nef associates with and inhibits apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that forms a common and key signalling intermediate in the Fas and tumour-necrosis factor-α (TNFα) death-signalling pathways.
Lipid rafts and HIV-1: from viral entry to assembly of progeny virions.
  • S. Campbell, S. Crowe, J. Mak
  • Biology, Medicine
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
  • 2001
HIV-1 Nef inhibits a common activation pathway in NIH-3T3 cells.
The Nef protein of primate lentiviruses
The high degree of understanding of at least some aspects of Nef action, as well as the importance of this viral gene product for disease induction, identify Nef as a valuable target for the development of novel antiviral therapies.
Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity
Binding and coprecipitation assays with short synthetic peptides corresponding to the proline-rich repeat sequence of Nef and the SH2, SH3, or SH2 and SH3 domains of Lck revealed that the interaction between these two proteins is at least in part mediated by the pro line repeat sequences of Nf and theSH3 domain of Lk.
Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity.
In inspection of diverse Nef proteins from HIV-1, HIV-2, and simian immunodeficiency virus, a well-conserved sequence in the central region of the C-terminal, solvent-exposed loop of Nef that conforms to the consensus sequence of the dileucine-based sorting motifs found in cellular transmembrane proteins is revealed.
Mechanisms of HIV‐1 to escape from the host immune surveillance
HIV is able to down‐regulate major histocompatibility complex type I (MHC‐I) on the surface of the host cell and provides protection to natural killer cells that attack cells with little or no MHC‐ I on the cell surface.
Myristoylation-dependent binding of HIV-1 Nef to CD4.
It is demonstrated that a baculovirus-expressed Nef-GST fusion protein interacts specifically with CD4, and this interaction requires co-expression in the same cell and is dependent on Nef myristoylation.