Consequences of HLA-associated mutations in HIV-1 subtype C Nef on HLA-I downregulation ability.
CTL responses
HIV-1 Nef
Nef-mediated HLA-I downregulation
mutations
Journal
Journal of medical virology
ISSN: 1096-9071
Titre abrégé: J Med Virol
Pays: United States
ID NLM: 7705876
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
08
10
2019
accepted:
07
01
2020
pubmed:
17
1
2020
medline:
13
7
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Identification of CD8+ T lymphocyte (CTL) escape mutations that compromise the pathogenic functions of the Nef protein may be relevant for an HIV-1 attenuation-based vaccine. Previously, HLA-associated mutations 102H, 105R, 108D, and 199Y were individually statistically associated with decreased Nef-mediated HLA-I downregulation ability in a cohort of 298 HIV-1 subtype C infected individuals. In the present study, these mutations were introduced by site-directed mutagenesis into different patient-derived Nef sequence backgrounds of high similarity to the consensus C Nef sequence, and their ability to downregulate HLA-I was measured by flow cytometry in a CEM-derived T cell line. A substantial negative effect of 199Y on HLA-I downregulation and Nef expression was observed, while 102H and 105R displayed negative effects on HLA-I downregulation ability and Nef expression to a lesser extent. The total magnitude of CTL responses in individuals harboring the 199Y mutation was lower than those without the mutation, although this was not statistically significant. Overall, a modest positive relationship between Nef-mediated HLA-I downregulation ability and total magnitude of CTL responses was observed, suggesting that there is a higher requirement for HLA-I downregulation with increased CTL pressure. These results highlight a region of Nef that could be targeted by vaccine-induced CTL to reduce HLA-I downregulation and maximize CTL efficacy.
Substances chimiques
nef Gene Products, Human Immunodeficiency Virus
0
nef protein, Human immunodeficiency virus 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1182-1190Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals, Inc.
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