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Journal of Virology, March 2009, p. 2743-2755, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02265-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HLA-B57/B*5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition{triangledown}

Toshiyuki Miura,1,2,3* Mark A. Brockman,1,3 Arne Schneidewind,1,3 Michael Lobritz,4 Florencia Pereyra,1,3 Almas Rathod,1 Brian L. Block,1 Zabrina L. Brumme,1,3 Chanson J. Brumme,1 Brett Baker,1 Alissa C. Rothchild,1 Bin Li,1,3 Alicja Trocha,1,2 Emily Cutrell,1 Nicole Frahm,1,3 Christian Brander,1,3 Ildiko Toth,1 Eric J. Arts,4 Todd M. Allen,1,3 and Bruce D. Walker1,2,3*

Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129,1 Howard Hughes Medical Institute, Chevy Chase, Maryland,2 Harvard Medical School, Boston, Massachusetts,3 Case Western Reserve University, Cleveland, Ohio4

Received 29 October 2008/ Accepted 22 December 2008

Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag240-249 TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.

* Corresponding author. Mailing address: Ragon Institute, Massachusetts General Hospital, 149 13th St., Room 5212, Charlestown, MA 02129. Phone for Bruce D. Walker: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}partners.org. Phone for Toshiyuki Miura: (617) 643-2836. Fax: (617) 726-5411. E-mail: miura523{at}hotmail.com

{triangledown} Published ahead of print on 30 December 2008.

Journal of Virology, March 2009, p. 2743-2755, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02265-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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