Immune selection in vitro reveals human immunodeficiency virus type 1 Nef sequence motifs important for its immune evasion function in vivo.

Journal of Virology
Martha LewisOtto O Yang

Abstract

Human immunodeficiency virus type 1 (HIV-1) Nef downregulates major histocompatibility complex class I (MHC-I), impairing the clearance of infected cells by CD8(+) cytotoxic T lymphocytes (CTLs). While sequence motifs mediating this function have been determined by in vitro mutagenesis studies of laboratory-adapted HIV-1 molecular clones, it is unclear whether the highly variable Nef sequences of primary isolates in vivo rely on the same sequence motifs. To address this issue, nef quasispecies from nine chronically HIV-1-infected persons were examined for sequence evolution and altered MHC-I downregulatory function under Gag-specific CTL immune pressure in vitro. This selection resulted in decreased nef diversity and strong purifying selection. Site-by-site analysis identified 13 codons undergoing purifying selection and 1 undergoing positive selection. Of the former, only 6 have been reported to have roles in Nef function, including 4 associated with MHC-I downregulation. Functional testing of naturally occurring in vivo polymorphisms at the 7 sites with no previously known functional role revealed 3 mutations (A84D, Y135F, and G140R) that ablated MHC-I downregulation and 3 (N52A, S169I, and V180E) that partially impaired MHC-...Continue Reading

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Citations

Jan 8, 2013·Retrovirology·Philip MwimanziTakamasa Ueno
Sep 18, 2013·Retrovirology·Jaclyn K MannZabrina L Brumme
Mar 16, 2013·Virology·Philip MwimanziTakamasa Ueno
Jul 17, 2015·Journal of Virology·Mako ToyodaTakamasa Ueno
Jun 27, 2014·Journal of Virology·Xiaomei T KuangMark A Brockman
Sep 6, 2014·Expert Review of Anti-infective Therapy·Nadia T Sebastian, Kathleen L Collins
Jan 17, 2020·Journal of Medical Virology·Jaclyn K MannThumbi Ndung'u
Oct 25, 2017·Journal of Neurovirology·Susanna L LamersMichael S McGrath
Jan 13, 2018·Journal of Virology·Zachary EndeEric Hunter

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