ArticleRetrovirology2012
Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function.
Article in Retrovirology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 16 citations in OpenAlex.
- Multifunctional Roles of the N-Terminal Region of HIV-1Journal of virology · 2019Article
- HLA-DQB1*06 and breadth of Nef core region-specific T-cell response are associated with slow disease progression in antiretroviral therapy-naive Chinese HIV-1 subtype B patients.Human vaccines & immunotherapeutics · 2017Article
- The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor.Journal of virology · 2016Article
- Hallmarks of HIV-1 pathogenesis are modulated by Nef's Secretion Modification Region.Journal of AIDS & clinical research · 2015Article
- A Conserved GPG-Motif in the HIV-1 Nef Core Is Required for Principal Nef-Activities.PloS one · 2015Article
- HIV-1 Nef and Vpu are functionally redundant broad-spectrum modulators of cell surface receptors, including tetraspanins.Journal of virology · 2014Article
- Short communication: HIV-1 Nef protein carries multiple epitopes suitable for induction of cellular immunity for an HIV vaccine in Africa.AIDS research and human retroviruses · 2014Article
- Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody.Retrovirology · 2014Article
- Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms.Retrovirology · 2013Article
- Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes.Retrovirology · 2013Article
- Overlapping effector interfaces define the multiple functions of the HIV-1 Nef polyproline helix.Retrovirology · 2012Article
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Authors and funding
11 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region.
resultsThe dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non-canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF→AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef's association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck.
conclusionBased on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef.
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