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Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in Human Immunodeficiency Virus Type 1 infection
Journal article   Open access   Peer reviewed

Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in Human Immunodeficiency Virus Type 1 infection

T.M. Allen, M. Altfeld, X.G. Yu, K.M. O'Sullivan, M. Lichterfeld, S. Le Gall, M. John, B.R. Mothe, P.K. Lee, E.T. Kalife, …
Journal of Virology, Vol.78(13), pp.7069-7078
2004
DOI: https://doi.org/10.1128/​JVI.78.13.7069-7078.2004
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Abstract

Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8+ T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.

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