Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA

Alasdair Leslie, Daniel Kavanagh, Isobella Honeyborne, Katja Pfafferott, Charles Edwards, Tilly Pillay, Louise Hilton, Christina Thobakgale, Danni Ramduth, Rika Draenert, Sylvie Le Gall, Graz Luzzi, Anne Edwards, Christian Brander, Andrew K Sewell, Sarah Moore, James Mullins, Corey Moore, Simon Mallal, Nina BhardwajKarina Yusim, Rodney Phillips, Paul Klenerman, Bette Korber, Photini Kiepiela, Bruce Walker, Philip Goulder

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181 Citations (Scopus)

Abstract

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of negatively associated or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Original languageEnglish
Pages (from-to)891 - 902
Number of pages12
JournalJournal of Experimental Medicine
Volume201
Issue number6
Publication statusPublished - 2005
Externally publishedYes

Cite this

Leslie, A., Kavanagh, D., Honeyborne, I., Pfafferott, K., Edwards, C., Pillay, T., Hilton, L., Thobakgale, C., Ramduth, D., Draenert, R., Le Gall, S., Luzzi, G., Edwards, A., Brander, C., Sewell, A. K., Moore, S., Mullins, J., Moore, C., Mallal, S., ... Goulder, P. (2005). Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. Journal of Experimental Medicine, 201(6), 891 - 902.