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¹ Peter Medawar Building, University of Oxford, Oxford OX13SY, UK
² Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, MA 02129
³ HPP, The Doris Duke Medical Research Institute, University of Natal, Durban 4015, South Africa
⁴ Department of Genitourinary Medicine, High Wycombe General Hospital, Buckinghamshire HP11 2TT, UK
⁵ The Harrison Clinic, Radcliffe Infirmary, Oxford OX2 6HE, UK
⁶ Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195
⁷ Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth WA 6000, Australia
⁸ Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545

CORRESPONDENCE Philip Goulder: Philip.goulder{at}ndm.ox.ac.uk

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.

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