This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schneidewind, A.
Right arrow Articles by Allen, T. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schneidewind, A.
Right arrow Articles by Allen, T. M.

 Previous Article  |  Next Article 

Journal of Virology, June 2008, p. 5594-5605, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02356-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Structural and Functional Constraints Limit Options for Cytotoxic T-Lymphocyte Escape in the Immunodominant HLA-B27-Restricted Epitope in Human Immunodeficiency Virus Type 1 Capsid{triangledown}

Arne Schneidewind,1,{dagger} Mark A. Brockman,1,2,{dagger} John Sidney,3 Yaoyu E. Wang,1 Huabiao Chen,1,2 Todd J. Suscovich,1 Bin Li,1 Rahma I. Adam,1 Rachel L. Allgaier,1 Bianca R. Mothé,4 Thomas Kuntzen,1 Cesar Oniangue-Ndza,1 Alicja Trocha,1 Xu G. Yu,1 Christian Brander,1 Alessandro Sette,3 Bruce D. Walker,1,2 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 La Jolla Institute for Allergy and Immunology, La Jolla, California,3 Department of Biological Sciences, California State University, San Marcos, California4

Received 31 October 2007/ Accepted 17 March 2008

Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8+ cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK263-272) in p24/Gag. Viral escape in KK10 typically occurs through development of an R264K substitution in conjunction with the upstream compensatory mutation S173A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R264 have been observed, but factors dictating the preferential selection of R264K remain unclear. Here we illustrate that while all observed R264 mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R264K. Importantly, however, none of these mutants replicated as well as an R264K variant containing the compensatory mutation S173A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R264K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R264K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R264K is due primarily to the ability of the S173A-compensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.

* 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 2 April 2008.

{dagger} Both authors contributed equally.

Journal of Virology, June 2008, p. 5594-5605, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02356-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Thobakgale, C. F., Prendergast, A., Crawford, H., Mkhwanazi, N., Ramduth, D., Reddy, S., Molina, C., Mncube, Z., Leslie, A., Prado, J., Chonco, F., Mphatshwe, W., Tudor-Williams, G., Jeena, P., Blanckenberg, N., Dong, K., Kiepiela, P., Coovadia, H., Ndung'u, T., Walker, B. D., Goulder, P. J. R. (2009). Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection. J. Virol. 83: 10234-10244 [Abstract] [Full Text]  
  • Loffredo, J. T., Sidney, J., Bean, A. T., Beal, D. R., Bardet, W., Wahl, A., Hawkins, O. E., Piaskowski, S., Wilson, N. A., Hildebrand, W. H., Watkins, D. I., Sette, A. (2009). Two MHC Class I Molecules Associated with Elite Control of Immunodeficiency Virus Replication, Mamu-B*08 and HLA-B*2705, Bind Peptides with Sequence Similarity. J. Immunol. 182: 7763-7775 [Abstract] [Full Text]  
  • Matthews, P. C., Leslie, A. J., Katzourakis, A., Crawford, H., Payne, R., Prendergast, A., Power, K., Kelleher, A. D., Klenerman, P., Carlson, J., Heckerman, D., Ndung'u, T., Walker, B. D., Allen, T. M., Pybus, O. G., Goulder, P. J. R. (2009). HLA Footprints on Human Immunodeficiency Virus Type 1 Are Associated with Interclade Polymorphisms and Intraclade Phylogenetic Clustering. J. Virol. 83: 4605-4615 [Abstract] [Full Text]  
  • Wang, Y. E., Li, B., Carlson, J. M., Streeck, H., Gladden, A. D., Goodman, R., Schneidewind, A., Power, K. A., Toth, I., Frahm, N., Alter, G., Brander, C., Carrington, M., Walker, B. D., Altfeld, M., Heckerman, D., Allen, T. M. (2009). Protective HLA Class I Alleles That Restrict Acute-Phase CD8+ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1. J. Virol. 83: 1845-1855 [Abstract] [Full Text]  
  • Prado, J. G., Honeyborne, I., Brierley, I., Puertas, M. C., Martinez-Picado, J., Goulder, P. J. R. (2009). Functional Consequences of Human Immunodeficiency Virus Escape from an HLA-B*13-Restricted CD8+ T-Cell Epitope in p1 Gag Protein. J. Virol. 83: 1018-1025 [Abstract] [Full Text]  
  • Miura, T., Brockman, M. A., Brumme, Z. L., Brumme, C. J., Pereyra, F., Trocha, A., Block, B. L., Schneidewind, A., Allen, T. M., Heckerman, D., Walker, B. D. (2009). HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1. J. Virol. 83: 140-149 [Abstract] [Full Text]  
  • Gomez, P., Mavian, C., Galocha, B., Garcia-Medel, N., Lopez de Castro, J. A. (2009). Presentation of Cytosolically Stable Peptides by HLA-B27 Is Not Dependent on the Canonic Interactions of N-Terminal Basic Residues in the A Pocket. J. Immunol. 182: 446-455 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»