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

The Differential Ability of HLA B^*5701⁺ Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous Viral gag Sequences

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,¹ Science Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland²

Received 17 September 2002/ Accepted 18 March 2003

Although the HLA B^*5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57⁺ progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8⁺ T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B^*57⁺ patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8⁺ T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4⁺ T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8⁺ T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B^*5701⁺ HIV-infected patients. Qualitative features of the virus-specific CD8⁺ T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B^*5701⁺ LTNPs and progressors to restrict virus replication.

This article has been cited by other articles:

• Emu, B., Sinclair, E., Hatano, H., Ferre, A., Shacklett, B., Martin, J. N., McCune, J. M., Deeks, S. G. (2008). HLA Class I-Restricted T-Cell Responses May Contribute to the Control of Human Immunodeficiency Virus Infection, but Such Responses Are Not Always Necessary for Long-Term Virus Control. J. Virol. 82: 5398-5407 [Abstract] [Full Text]  
• Maness, N. J., Yant, L. J., Chung, C., Loffredo, J. T., Friedrich, T. C., Piaskowski, S. M., Furlott, J., May, G. E., Soma, T., Leon, E. J., Wilson, N. A., Piontkivska, H., Hughes, A. L., Sidney, J., Sette, A., Watkins, D. I. (2008). Comprehensive Immunological Evaluation Reveals Surprisingly Few Differences between Elite Controller and Progressor Mamu-B*17-Positive Simian Immunodeficiency Virus-Infected Rhesus Macaques. J. Virol. 82: 5245-5254 [Abstract] [Full Text]  
• Peters, H. O., Mendoza, M. G., Capina, R. E., Luo, M., Mao, X., Gubbins, M., Nagelkerke, N. J. D., MacArthur, I., Sheardown, B. B., Kimani, J., Wachihi, C., Thavaneswaran, S., Plummer, F. A. (2008). An Integrative Bioinformatic Approach for Studying Escape Mutations in Human Immunodeficiency Virus Type 1 gag in the Pumwani Sex Worker Cohort. J. Virol. 82: 1980-1992 [Abstract] [Full Text]  
• Brockman, M. A., Schneidewind, A., Lahaie, M., Schmidt, A., Miura, T., DeSouza, I., Ryvkin, F., Derdeyn, C. A., Allen, S., Hunter, E., Mulenga, J., Goepfert, P. A., Walker, B. D., Allen, T. M. (2007). Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A. J. Virol. 81: 12608-12618 [Abstract] [Full Text]  
• Navis, M., Schellens, I., van Baarle, D., Borghans, J., van Swieten, P., Miedema, F., Kootstra, N., Schuitemaker, H. (2007). Viral Replication Capacity as a Correlate of HLA B57/B5801-Associated Nonprogressive HIV-1 Infection. J. Immunol. 179: 3133-3143 [Abstract] [Full Text]  
• Frater, A. J., Brown, H., Oxenius, A., Gunthard, H. F., Hirschel, B., Robinson, N., Leslie, A. J., Payne, R., Crawford, H., Prendergast, A., Brander, C., Kiepiela, P., Walker, B. D., Goulder, P. J. R., McLean, A., Phillips, R. E., and the Swiss HIV-Cohort Study, (2007). Effective T-Cell Responses Select Human Immunodeficiency Virus Mutants and Slow Disease Progression. J. Virol. 81: 6742-6751 [Abstract] [Full Text]  
• Blankson, J. N., Bailey, J. R., Thayil, S., Yang, H.-C., Lassen, K., Lai, J., Gandhi, S. K., Siliciano, J. D., Williams, T. M., Siliciano, R. F. (2007). Isolation and Characterization of Replication-Competent Human Immunodeficiency Virus Type 1 from a Subset of Elite Suppressors. J. Virol. 81: 2508-2518 [Abstract] [Full Text]  
• Yu, X. G., Lichterfeld, M., Chetty, S., Williams, K. L., Mui, S. K., Miura, T., Frahm, N., Feeney, M. E., Tang, Y., Pereyra, F., LaBute, M. X., Pfafferott, K., Leslie, A., Crawford, H., Allgaier, R., Hildebrand, W., Kaslow, R., Brander, C., Allen, T. M., Rosenberg, E. S., Kiepiela, P., Vajpayee, M., Goepfert, P. A., Altfeld, M., Goulder, P. J. R., Walker, B. D. (2007). Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes. J. Virol. 81: 1619-1631 [Abstract] [Full Text]  
• Wojcechowskyj, J. A., Yant, L. J., Wiseman, R. W., O'Connor, S. L., O'Connor, D. H. (2007). Control of Simian Immunodeficiency Virus SIVmac239 Is Not Predicted by Inheritance of Mamu-B*17-Containing Haplotypes. J. Virol. 81: 406-410 [Abstract] [Full Text]  
• Leslie, A., Price, D. A., Mkhize, P., Bishop, K., Rathod, A., Day, C., Crawford, H., Honeyborne, I., Asher, T. E., Luzzi, G., Edwards, A., Rosseau, C. M., Mullins, J. I., Tudor-Williams, G., Novelli, V., Brander, C., Douek, D. C., Kiepiela, P., Walker, B. D., Goulder, P. J. R. (2006). Differential Selection Pressure Exerted on HIV by CTL Targeting Identical Epitopes but Restricted by Distinct HLA Alleles from the Same HLA Supertype. J. Immunol. 177: 4699-4708 [Abstract] [Full Text]  
• Gillespie, G. M. A., Stewart-Jones, G., Rengasamy, J., Beattie, T., Bwayo, Job. J., Plummer, F. A., Kaul, R., McMichael, A. J., Easterbrook, P., Dong, T., Jones, E. Y., Rowland-Jones, S. L. (2006). Strong TCR Conservation and Altered T Cell Cross-Reactivity Characterize a B*57-Restricted Immune Response in HIV-1 Infection. J. Immunol. 177: 3893-3902 [Abstract] [Full Text]  
• Yeh, W. W., Cale, E. M., Jaru-Ampornpan, P., Lord, C. I., Peyerl, F. W., Letvin, N. L. (2006). Compensatory substitutions restore normal core assembly in simian immunodeficiency virus isolates with gag epitope cytotoxic T-lymphocyte escape mutations.. J. Virol. 80: 8168-8177 [Abstract] [Full Text]  
• Betts, M. R., Nason, M. C., West, S. M., De Rosa, S. C., Migueles, S. A., Abraham, J., Lederman, M. M., Benito, J. M., Goepfert, P. A., Connors, M., Roederer, M., Koup, R. A. (2006). HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781-4789 [Abstract] [Full Text]  
• Bailey, J. R., Williams, T. M., Siliciano, R. F., Blankson, J. N. (2006). Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J. Exp. Med. 203: 1357-1369 [Abstract] [Full Text]  
• Turnbull, E. L., Lopes, A. R., Jones, N. A., Cornforth, D., Newton, P., Aldam, D., Pellegrino, P., Turner, J., Williams, I., Wilson, C. M., Goepfert, P. A., Maini, M. K., Borrow, P. (2006). HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently. J. Immunol. 176: 6130-6146 [Abstract] [Full Text]  
• Martinez-Picado, J., Prado, J. G., Fry, E. E., Pfafferott, K., Leslie, A., Chetty, S., Thobakgale, C., Honeyborne, I., Crawford, H., Matthews, P., Pillay, T., Rousseau, C., Mullins, J. I., Brander, C., Walker, B. D., Stuart, D. I., Kiepiela, P., Goulder, P. (2006). Fitness Cost of Escape Mutations in p24 Gag in Association with Control of Human Immunodeficiency Virus Type 1.. J. Virol. 80: 3617-3623 [Abstract] [Full Text]  
• Draenert, R., Allen, T. M., Liu, Y., Wrin, T., Chappey, C., Verrill, C. L., Sirera, G., Eldridge, R. L., Lahaie, M. P., Ruiz, L., Clotet, B., Petropoulos, C. J., Walker, B. D., Martinez-Picado, J. (2006). Constraints on HIV-1 evolution and immunodominance revealed in monozygotic adult twins infected with the same virus. J. Exp. Med. 203: 529-539 [Abstract] [Full Text]  
• Jansen, C. A., De Cuyper, I. M., Hooibrink, B., van der Bij, A. K., van Baarle, D., Miedema, F. (2006). Prognostic value of HIV-1 Gag-specific CD4+ T-cell responses for progression to AIDS analyzed in a prospective cohort study. Blood 107: 1427-1433 [Abstract] [Full Text]  
• Allen, T. M., Altfeld, M., Geer, S. C., Kalife, E. T., Moore, C., O'Sullivan, K. M., DeSouza, I., Feeney, M. E., Eldridge, R. L., Maier, E. L., Kaufmann, D. E., Lahaie, M. P., Reyor, L., Tanzi, G., Johnston, M. N., Brander, C., Draenert, R., Rockstroh, J. K., Jessen, H., Rosenberg, E. S., Mallal, S. A., Walker, B. D. (2005). Selective Escape from CD8+ T-Cell Responses Represents a Major Driving Force of Human Immunodeficiency Virus Type 1 (HIV-1) Sequence Diversity and Reveals Constraints on HIV-1 Evolution. J. Virol. 79: 13239-13249 [Abstract] [Full Text]  
• Feeney, M. E., Tang, Y., Pfafferott, K., Roosevelt, K. A., Draenert, R., Trocha, A., Yu, X. G., Verrill, C., Allen, T., Moore, C., Mallal, S., Burchett, S., McIntosh, K., Pelton, S. I., St. John, M. A., Hazra, R., Klenerman, P., Altfeld, M., Walker, B. D., Goulder, P. J. R. (2005). HIV-1 Viral Escape in Infancy Followed by Emergence of a Variant-Specific CTL Response. J. Immunol. 174: 7524-7530 [Abstract] [Full Text]  
• O'Connor, D. H., McDermott, A. B., Krebs, K. C., Dodds, E. J., Miller, J. E., Gonzalez, E. J., Jacoby, T. J., Yant, L., Piontkivska, H., Pantophlet, R., Burton, D. R., Rehrauer, W. M., Wilson, N., Hughes, A. L., Watkins, D. I. (2004). A Dominant Role for CD8+-T-Lymphocyte Selection in Simian Immunodeficiency Virus Sequence Variation. J. Virol. 78: 14012-14022 [Abstract] [Full Text]  
• Draenert, R., Le Gall, S., Pfafferott, K. J., Leslie, A. J., Chetty, P., Brander, C., Holmes, E. C., Chang, S.-C., Feeney, M. E., Addo, M. M., Ruiz, L., Ramduth, D., Jeena, P., Altfeld, M., Thomas, S., Tang, Y., Verrill, C. L., Dixon, C., Prado, J. G., Kiepiela, P., Martinez-Picado, J., Walker, B. D., Goulder, P. J.R. (2004). Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection. J. Exp. Med. 199: 905-915 [Abstract] [Full Text]  
• Draenert, R., Verrill, C. L., Tang, Y., Allen, T. M., Wurcel, A. G., Boczanowski, M., Lechner, A., Kim, A. Y., Suscovich, T., Brown, N. V., Addo, M. M., Walker, B. D. (2004). Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection. J. Virol. 78: 630-641 [Abstract] [Full Text]