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      HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification

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          The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8 + T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ∼30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ∼60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.

          Graphical Abstract


          • HLA class I variants drive selection pressures on Gag to limit epitope production

          • The strength of the selective pressure is positively correlated to HLA frequencies

          • HIV adaptation to limit epitope production occurs at subtype-specific HIV motifs

          • HIV adapts in a predictable way to HLA frequencies in newly infected populations


          CD8 + T cell responses against HIV-1 effectively delay disease progression in a minority of patients with relatively rare HLA variants but are ineffective in most. Here, Tenzer et al. identify fundamental HIV-1 adaptation to the conserved human antigen-processing machinery that feeds epitopes to HLA. This adaptation occurs at subtype-specific motifs, facilitates subtype diversification, is predictable, and results in CD8 epitope abundances that correlate inversely with the HLA allele frequencies in affected populations. Thus, HIV vaccine immunogenicity might be increased by unnatural substitutions at subtype-specific motifs.

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          Most cited references 33

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          Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover

          The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)–B27 patients. To understand further the nature of CD8+ T cell–mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27–restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.
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            Adaptation of HIV-1 to human leukocyte antigen class I.

            The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.
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              Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1.

              Mutational escape by human immunodeficiency virus (HIV) from cytotoxic T-lymphocyte (CTL) recognition is a major challenge for vaccine design. However, recent studies suggest that CTL escape may carry a sufficient cost to viral replicative capacity to facilitate subsequent immune control of a now attenuated virus. In order to examine how limitations can be imposed on viral escape, the epitope TSTLQEQIGW (TW10 [Gag residues 240 to 249]), presented by two HLA alleles associated with effective control of HIV, HLA-B*57 and -B*5801, was investigated. The in vitro experiments described here demonstrate that the dominant TW10 escape mutation, T242N, reduces viral replicative capacity. Structural analysis reveals that T242 plays a critical role in defining the start point and in stabilizing helix 6 within p24 Gag, ensuring that escape occurs at a significant cost. A very similar role is played by Thr-180, which is also an escape residue, but within a second p24 Gag epitope associated with immune control. Analysis of HIV type 1 gag in 206 B*57/5801-positive subjects reveals three principle alternative TW10-associated variants, and each is strongly linked to concomitant additional variants within p24 Gag, suggesting that functional constraints operate against their occurrence alone. The extreme conservation of p24 Gag and the predictable nature of escape variation resulting from these tight functional constraints indicate that p24 Gag may be a critical immunogen in vaccine design and suggest novel vaccination strategies to limit viral escape options from such epitopes.

                Author and article information

                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                24 April 2014
                24 April 2014
                : 7
                : 2
                : 448-463
                [1 ]Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
                [2 ]Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK
                [3 ]Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK
                [4 ]Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA
                [5 ]Institut National de la Santé et de la Recherche Médicale, Unité 1151, Centre National de la Recherche Scientifique, UMR8253, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France
                [6 ]Africa Centre for Health and Population Studies, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, KwaZulu-Natal 3935, South Africa
                [7 ]Research Department of Infection, University College London, Cruciform Building, 90 Gower Street, London WC1E 6BT, UK
                [8 ]Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Blegdamsvej 9, 2100 Kbh Ø Copenhagen, Denmark
                [9 ]Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK
                [10 ]Office of the Regius Professor of Medicine, The Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Drive 1, Oxford OX3 7LF, UK
                Author notes
                []Corresponding author astrid.iversen@
                © 2014 The Authors

                This is an open access article under the CC BY-NC-ND license (


                Cell biology


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