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Journal of Virology, November 2007, p. 12382-12393, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01543-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Escape from the Dominant HLA-B27-Restricted Cytotoxic T-Lymphocyte Response in Gag Is Associated with a Dramatic Reduction in Human Immunodeficiency Virus Type 1 Replication{triangledown}

Arne Schneidewind,1,{dagger} Mark A. Brockman,1,2,{dagger} Ruifeng Yang,3 Rahma I. Adam,1 Bin Li,1 Sylvie Le Gall,1 Charles R. Rinaldo,4 Sharon L. Craggs,5,{ddagger} Rachel L. Allgaier,1 Karen A. Power,1 Thomas Kuntzen,1 Chang-Shung Tung,6 Montiago X. LaBute,6 Sandra M. Mueller,7 Thomas Harrer,7 Andrew J. McMichael,5 Philip J. R. Goulder,1,8 Christopher Aiken,3 Christian Brander,1 Anthony D. Kelleher,9 and Todd M. Allen1*

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,1 Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,2 Department of Microbiology and Immunology, Vanderbilt University School of Medicine, A-5301 Medical Center North, Nashville, Tennessee,3 Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania,4 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom,5 Theoretical Biology and Biophysics, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico,6 Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany,7 Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford, United Kingdom,8 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia9

Received 15 July 2007/ Accepted 28 August 2007

Human leukocyte antigen (HLA)-B27-positive subjects are uncommon in their ability to control infection with human immunodeficiency virus type 1 (HIV-1). However, late viral escape from a narrowly directed immunodominant Gag-specific CD8+ T-lymphocyte (CTL) response has been linked to AIDS progression in these individuals. Identifying the mechanism of the immune-mediated control may provide critical insights into HIV-1 vaccine development. Here, we illustrate that the CTL escape mutation R264K in the HLA-B27-restricted KK10 epitope in the capsid resulted in a significant defect in viral replication in vitro. The R264K variant was impaired in generating late reverse transcription products, indicating that replication was blocked at a postentry step. Notably, the R264K mutation was associated in vivo with the development of a rare secondary mutation, S173A, which restored viral replication in vitro. Furthermore, infectivity of the R264K variant was rescued by the addition of cyclosporine A or infection of a cyclophilin A-deficient cell line. These data demonstrate a severe functional defect imposed by the R264K mutation during an early step in viral replication that is likely due to the inability of this variant to replicate efficiently in the presence of normal levels of cyclophilin A. We conclude that the impact of the R264K substitution on capsid structure constrains viral escape and enables long-term maintenance of the dominant CTL response against B27-KK10, providing an explanation for the protective effect of HLA-B27 during HIV infection.

* Corresponding author. Mailing address: MGH-East, CNY 6625, 149 13th Street, Charlestown, MA 02129. Phone: (617) 726-7846. Fax: (617) 724-8586. E-mail: tallen2{at}partners.org

{triangledown} Published ahead of print on 5 September 2007.

{dagger} A.S. and M.A.B. contributed equally.

{ddagger} Present address: ReOx Ltd., Magdalen Centre, Oxford Science Park, Oxford, United Kingdom.

Journal of Virology, November 2007, p. 12382-12393, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01543-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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