CTL-mediated selective pressure influences dynamic evolution and pathogenic functions of HIV-1 Nef

The Journal of Immunology : Official Journal of the American Association of Immunologists
Takamasa UenoM Takiguchi

Abstract

HIV-1 Nef plays multiple roles in modulating immune responses, even though it is a dominant CTL target itself. How Nef accomplishes the balance between such conflicting selective pressures remains elusive. By genetic and functional studies, we found that Arg75Thr and Tyr85Phe mutations, located in a well-conserved proline-rich region in Nef, were differently associated with escape from CTL responses specific for two overlapping HLA-B35-restricted epitopes. CTLs specific for an epitope, that selected Tyr85Phe, were elicited earlier and had more potent functional avidities than did those that selected Arg75Thr. Although the double mutant could escape from both CTLs, the mutations are rarely observed in combination naturally. Introduction of both mutations reduced Nef's HLA class I down-regulation activity and increased the susceptibility of virus-infected cells to recognition by CTLs targeting other epitopes. Moreover, the mutant Nef was impaired in the association with activated cellular kinases and in the enhancement of viral replication. These results highlight CTL immunosurveillance as important modulators of Nef's biological activity in the infected host.

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Citations

Mar 31, 2009·AIDS Research and Human Retroviruses·Christine M RousseauJames I Mullins
May 14, 2010·Journal of Virology·Anke SpechtFrank Kirchhoff
Sep 12, 2015·Journal of Virology·Aniqa ShahidZabrina L Brumme
Aug 9, 2019·Virus Evolution·John P BartonThumbi Ndung'u
Jun 6, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Xiaoming SunMasafumi Takiguchi
Jul 17, 2015·Journal of Virology·Mako ToyodaTakamasa Ueno
Apr 22, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Chihiro MotozonoTakamasa Ueno
Apr 13, 2012·Journal of Virology·Mark A BrockmanZabrina L Brumme
Jun 27, 2014·Journal of Virology·Xiaomei T KuangMark A Brockman
Jan 17, 2020·Journal of Medical Virology·Jaclyn K MannThumbi Ndung'u
Mar 7, 2012·Future Virology·Denis R ChoperaZabrina L Brumme
Jan 8, 2013·Retrovirology·Philip MwimanziTakamasa Ueno
Jun 10, 2009·Retrovirology·Benjamin N BimberHa Youn Lee

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