Alkylating HIV-1 Nef - a potential way of HIV intervention

  title={Alkylating HIV-1 Nef - a potential way of HIV intervention},
  author={Yongjiu Jin and Xiaoping Zhang and C. Y. Cai and S. Burakoff},
  journal={AIDS Research and Therapy},
  pages={26 - 26}
BackgroundNef is a 27 KDa HIV-1 accessory protein. It downregulates CD4 from infected cell surface, a mechanism critical for efficient viral replication and pathogenicity. Agents that antagonize the Nef-mediated CD4 downregulation may offer a new class of drug to combat HIV infection and disease. TPCK (N-α-p-tosyl-L-phenylalanine chloromethyl ketone) and TLCK (N-α-p-tosyl-L-lysine chloromethyl ketone) are alkylation reagents that chemically modify the side chain of His or Cys residues in a… Expand
4 Citations
N-p-Tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibits HIV-1 by suppressing the activity of viral protease.
This study reports that N-p-Tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibits HIV-1 replication in a highly-conserved manner and shows significant synergistic inhibitory potential, suggesting the potential use of TPCK in cART regimen. Expand
Identification of a novel binding site between HIV type 1 Nef C-terminal flexible loop and AP2 required for Nef-mediated CD4 downregulation.
The data suggest a new model in the Nef-AP2 interaction in which the hydrophobic region in theNef C-loop with the dileucine motif and M168L170 motif binds to AP2(σ2), while the acidic motif E174 and D175 binds toAP2(α), which explains how Nef through the flexible loop connects CD4 to AP1 for constitutive CD4 downregulation. Expand
Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols.
Results are consistent with the view that the binding of PTT positions the peptide SH group to interfere with conserved disulfides clustered proximal to the CD4 binding site in gp120, leading to disulfide exchange in gp 120 and possibly gp41, rearrangement of the Env spike, and ultimately disruption of the viral membrane. Expand
Mass spectrometry based proteomic studies on viruses and hosts – A review
As more virus and host genomes are being sequenced, MS-based proteomics is becoming an indispensable tool for virology. Expand


HIV Nef-Mediated CD4 Down-Regulation Is Adaptor Protein Complex 2 Dependent1
D dileucine sorting motif-dependent endocytosis of Nef and CD4 are also AP-2 dependent, and PMA-induced CD4 down-regulation was blocked by these two inhibitors, demonstrating that HIV/SIV Nef-mediated CD4Down-regulation is AP- 2 dependent. Expand
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. Expand
The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR.
Using heteronuclear NMR spectroscopy, it is demonstrated that a 13-residue peptide from the cytoplasmic tail of CD4 binds to Nef protein, indicating that the binding ofCD4 and Hck SH3 to Naf are two compatible and slightly cooperative events. Expand
HIV-1 Nef Binds the DOCK2–ELMO1 Complex to Activate Rac and Inhibit Lymphocyte Chemotaxis
Proteomic data indicate that Nef targets a critical switch that regulates Rac GTPases downstream of chemokine- and antigen-initiated signaling pathways that enables Nef to influence multiple aspects of T cell function and thus provides an important mechanism by which Nef impacts pathogenesis by primate lentiviruses. Expand
Identification of the Nef-associated kinase as p21-activated kinase 2
Identification of NAK as PAK2 should now facilitate elucidation of its role as a mediator of the pathogenic effects of Nef, indicating the abundance of another cellular factor as the limiting factor in Nef-PAK2 complex formation. Expand
Lysine 144, a Ubiquitin Attachment Site in HIV-1 Nef, Is Required for Nef-Mediated CD4 Down-Regulation1
The in vivo ubiquitination assay showed that both HIV-1 and SIV Nef proteins expressed in Jurkat T cells and 293T cells were multiple ubiquitinated by ubiquitin-His, suggesting that ubiquitinations of Nef, particularly diubiquitination of the lysine 144, is necessary for Nef-mediated CD4 down-regulation. Expand
A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4
It is found that a sequence in the carboxy-terminal disordered loop of Nef is essential for downregulation of CD4 and for interaction with clathrin adaptor complexes. Expand
The physiological relevance of CD4 receptor down-modulation during HIV infection.
  • J. Lama
  • Biology, Medicine
  • Current HIV research
  • 2003
Recent findings indicate that efficient CD4 down-modulation is essential for the production of infectious particles, and highlight the importance of this function in HIV pathogenesis in vivo. Expand
Serine phosphorylation-independent downregulation of cell-surface CD4 by nef
A Moloney murine leukaemia virus-based retroviral vector is used in order to express the nef gene of HIV-1 in three lymphocytic cell lines expressing CD4, and it is found that cell-surface CD4 expression is inversely related to nef expression. Expand
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. Expand