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Journal of Virology, January 2009, p. 140-149, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01471-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1 {triangledown}

Toshiyuki Miura,1,2,3 Mark A. Brockman,1,2 Zabrina L. Brumme,1,2 Chanson J. Brumme,1 Florencia Pereyra,1,2 Alicja Trocha,1,3 Brian L. Block,1 Arne Schneidewind,1,2 Todd M. Allen,1,2 David Heckerman,4 and Bruce D. Walker1,2,3*

Partners AIDS Research Center, Massachusetts General Hospital, 13th St., BLD149, Charlestown, Massachusetts 02129,1 Harvard University Center for AIDS Research, Boston, Massachusetts 02115,2 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815,3 Microsoft Research, Redmond, Washington 980524

Received 14 July 2008/ Accepted 16 October 2008

Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of "protective" class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP; n = 41) by constructing chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57+ EC (n = 18) demonstrated lower VRC than did viruses from B*57+ CP (n = 8, P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described "protective" alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure on gag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.

* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Room 5212, Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}partners.org

{triangledown} Published ahead of print on 29 October 2008.

Journal of Virology, January 2009, p. 140-149, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01471-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nou, E., Zhou, Y., Nou, D. D., Blankson, J. N. (2009). Effective Downregulation of HLA-A*2 and HLA-B*57 by Primary Human Immunodeficiency Virus Type 1 Isolates Cultured from Elite Suppressors. J. Virol. 83: 6941-6946 [Abstract] [Full Text]  
  • Miura, T., Brumme, C. J., Brockman, M. A., Brumme, Z. L., Pereyra, F., Block, B. L., Trocha, A., John, M., Mallal, S., Harrigan, P. R., Walker, B. D. (2009). HLA-Associated Viral Mutations Are Common in Human Immunodeficiency Virus Type 1 Elite Controllers. J. Virol. 83: 3407-3412 [Abstract] [Full Text]  
  • Miura, T., Brockman, M. A., Schneidewind, A., Lobritz, M., Pereyra, F., Rathod, A., Block, B. L., Brumme, Z. L., Brumme, C. J., Baker, B., Rothchild, A. C., Li, B., Trocha, A., Cutrell, E., Frahm, N., Brander, C., Toth, I., Arts, E. J., Allen, T. M., Walker, B. D. (2009). 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. J. Virol. 83: 2743-2755 [Abstract] [Full Text]  


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