Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes.
Anti-HIV Agents
/ pharmacology
CD4 Antigens
/ metabolism
Crystallography, X-Ray
Down-Regulation
HIV-1
/ enzymology
Immune Evasion
Major Histocompatibility Complex
Membrane Proteins
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Protein Kinases
/ drug effects
Protein Transport
Structure-Activity Relationship
nef Gene Products, Human Immunodeficiency Virus
/ chemistry
AIDS
Btk
CD4
HIV-1 Nef
Hck
Itk
MHC-I
SH2 domain
SH3 domain
Src homology 2 domain (SH2 domain)
Src homology 3 domain (SH3 domain)
Src-family kinases
Tec-family kinases
bimolecular fluorescence complementation (BiFC)
dimerization
endocytosis
human immunodeficiency virus (HIV)
infectious disease
major histocompatibility complex (MHC)
protein-protein interaction
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
30 10 2020
30 10 2020
Historique:
received:
14
07
2020
revised:
28
08
2020
pubmed:
31
8
2020
medline:
30
3
2021
entrez:
31
8
2020
Statut:
ppublish
Résumé
Antiretroviral therapy has revolutionized the treatment of AIDS, turning a deadly disease into a manageable chronic condition. Life-long treatment is required because existing drugs do not eradicate HIV-infected cells. The emergence of drug-resistant viral strains and uncertain vaccine prospects highlight the pressing need for new therapeutic approaches with the potential to clear the virus. The HIV-1 accessory protein Nef is essential for viral pathogenesis, making it a promising target for antiretroviral drug discovery. Nef enhances viral replication and promotes immune escape of HIV-infected cells but lacks intrinsic enzymatic activity. Instead, Nef works through diverse interactions with host cell proteins primarily related to kinase signaling pathways and endosomal trafficking. This review emphasizes the structure, function, and biological relevance of Nef interactions with host cell protein-tyrosine kinases in the broader context of Nef functions related to enhancement of the viral life cycle and immune escape. Drug discovery targeting Nef-mediated kinase activation has allowed identification of promising inhibitors of multiple Nef functions. Pharmacological inhibitors of Nef-induced MHC-I down-regulation restore the adaptive immune response to HIV-infected cells
Identifiants
pubmed: 32862141
pii: S0021-9258(17)48918-6
doi: 10.1074/jbc.REV120.012317
pmc: PMC7606690
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
CD4 Antigens
0
Membrane Proteins
0
Protein Kinase Inhibitors
0
nef Gene Products, Human Immunodeficiency Virus
0
Protein Kinases
EC 2.7.-
Banques de données
PDB
['1EFN', '1QA4', '1QA5', '1AVZ', '2NEF', '4U5W', '1QCF', '4EN2', '4NEE', '6URI', '2SRC']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
15158-15171Subventions
Organisme : NIAID NIH HHS
ID : R56 AI102724
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI102724
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233978
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM086507
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI057083
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM101135
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI152677
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI126617
Pays : United States
Informations de copyright
© 2020 Staudt et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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