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 Draenert, R.
Right arrow Articles by Walker, B. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Draenert, R.
Right arrow Articles by Walker, B. D.

 Previous Article  |  Next Article 

Journal of Virology, January 2004, p. 630-641, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.630-641.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection

R. Draenert,1 C. L. Verrill,1 Y. Tang,1 T. M. Allen,1 A. G. Wurcel,1,2 M. Boczanowski,1 A. Lechner,3 A. Y. Kim,1 T. Suscovich,1 N. V. Brown,1 M. M. Addo,1 and B. D. Walker1*

Howard Hughes Medical Institute, Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School Division of AIDS,1 Lemuel Shattuck Hospital,2 Molecular Endocrinology, Massachusetts General Hospital, Boston, Massachusetts3

Received 30 June 2003/ Accepted 12 September 2003

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/µl) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/106 peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

* Corresponding author. Mailing address: Partners AIDS Research Center, MGH-East, 149 13th St., Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}helix.mgh.harvard.edu.

Journal of Virology, January 2004, p. 630-641, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.630-641.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Migueles, S. A., Weeks, K. A., Nou, E., Berkley, A. M., Rood, J. E., Osborne, C. M., Hallahan, C. W., Cogliano-Shutta, N. A., Metcalf, J. A., McLaughlin, M., Kwan, R., Mican, J. M., Davey, R. T. Jr., Connors, M. (2009). Defective Human Immunodeficiency Virus-Specific CD8+ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy. J. Virol. 83: 11876-11889 [Abstract] [Full Text]  
  • Brainard, D. M., Seung, E., Frahm, N., Cariappa, A., Bailey, C. C., Hart, W. K., Shin, H.-S., Brooks, S. F., Knight, H. L., Eichbaum, Q., Yang, Y.-G., Sykes, M., Walker, B. D., Freeman, G. J., Pillai, S., Westmoreland, S. V., Brander, C., Luster, A. D., Tager, A. M. (2009). Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice. J. Virol. 83: 7305-7321 [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]  
  • Lichterfeld, M., Mou, D., Cung, T. D. H., Williams, K. L., Waring, M. T., Huang, J., Pereyra, F., Trocha, A., Freeman, G. J., Rosenberg, E. S., Walker, B. D., Yu, X. G. (2008). Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors. Blood 112: 3679-3687 [Abstract] [Full Text]  
  • Li, S., Gowans, E. J., Chougnet, C., Plebanski, M., Dittmer, U. (2008). Natural Regulatory T Cells and Persistent Viral Infection. J. Virol. 82: 21-30 [Full Text]  
  • Goldwich, A., Hahn, S. S. C., Schreiber, S., Meier, S., Kampgen, E., Wagner, R., Lutz, M. B., Schubert, U. (2008). Targeting HIV-1 Gag into the Defective Ribosomal Product Pathway Enhances MHC Class I Antigen Presentation and CD8+ T Cell Activation. J. Immunol. 180: 372-382 [Abstract] [Full Text]  
  • Liu, Y., McNevin, J., Zhao, H., Tebit, D. M., Troyer, R. M., McSweyn, M., Ghosh, A. K., Shriner, D., Arts, E. J., McElrath, M. J., Mullins, J. I. (2007). Evolution of Human Immunodeficiency Virus Type 1 Cytotoxic T-Lymphocyte Epitopes: Fitness-Balanced Escape. J. Virol. 81: 12179-12188 [Abstract] [Full Text]  
  • Brainard, D. M., Tager, A. M., Misdraji, J., Frahm, N., Lichterfeld, M., Draenert, R., Brander, C., Walker, B. D., Luster, A. D. (2007). Decreased CXCR3+ CD8 T Cells in Advanced Human Immunodeficiency Virus Infection Suggest that a Homing Defect Contributes to Cytotoxic T-Lymphocyte Dysfunction. J. Virol. 81: 8439-8450 [Abstract] [Full Text]  
  • Wolfl, M., Kuball, J., Ho, W. Y., Nguyen, H., Manley, T. J., Bleakley, M., Greenberg, P. D. (2007). Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 110: 201-210 [Abstract] [Full Text]  
  • Lichterfeld, M., Yu, X. G., Mui, S. K., Williams, K. L., Trocha, A., Brockman, M. A., Allgaier, R. L., Waring, M. T., Koibuchi, T., Johnston, M. N., Cohen, D., Allen, T. M., Rosenberg, E. S., Walker, B. D., Altfeld, M. (2007). Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells after Early HIV-1 Infection. J. Virol. 81: 4199-4214 [Abstract] [Full Text]  
  • McKinnon, L. R., Ball, T. B., Wachihi, C., McLaren, P. J., Waruk, J. L. M., Mao, X., Ramdahin, S., Anzala, A. O., Kamene, J., Luo, M., Fowke, K. R., Plummer, F. A. (2007). Epitope Cross-Reactivity Frequently Differs between Central and Effector Memory HIV-Specific CD8+ T Cells. J. Immunol. 178: 3750-3756 [Abstract] [Full Text]  
  • Geldmacher, C., Currier, J. R., Herrmann, E., Haule, A., Kuta, E., McCutchan, F., Njovu, L., Geis, S., Hoffmann, O., Maboko, L., Williamson, C., Birx, D., Meyerhans, A., Cox, J., Hoelscher, M. (2007). CD8 T-Cell Recognition of Multiple Epitopes within Specific Gag Regions Is Associated with Maintenance of a Low Steady-State Viremia in Human Immunodeficiency Virus Type 1-Seropositive Patients. J. Virol. 81: 2440-2448 [Abstract] [Full Text]  
  • Manuel, E. R., Charini, W. A., Sen, P., Peyerl, F. W., Kuroda, M. J., Schmitz, J. E., Autissier, P., Sheeter, D. A., Torbett, B. E., Letvin, N. L. (2006). Contribution of T-Cell Receptor Repertoire Breadth to the Dominance of Epitope-Specific CD8+ T-Lymphocyte Responses. J. Virol. 80: 12032-12040 [Abstract] [Full Text]  
  • Liu, Y., McNevin, J., Cao, J., Zhao, H., Genowati, I., Wong, K., McLaughlin, S., McSweyn, M. D., Diem, K., Stevens, C. E., Maenza, J., He, H., Nickle, D. C., Shriner, D., Holte, S. E., Collier, A. C., Corey, L., McElrath, M. J., Mullins, J. I. (2006). Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection. J. Virol. 80: 9519-9529 [Abstract] [Full Text]  
  • Schneider-Schaulies, S., Dittmer, U. (2006). Silencing T cells or T-cell silencing: concepts in virus-induced immunosuppression. J. Gen. Virol. 87: 1423-1438 [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. JEM 203: 529-539 [Abstract] [Full Text]  
  • Urbani, S., Amadei, B., Cariani, E., Fisicaro, P., Orlandini, A., Missale, G., Ferrari, C. (2005). The Impairment of CD8 Responses Limits the Selection of Escape Mutations in Acute Hepatitis C Virus Infection. J. Immunol. 175: 7519-7529 [Abstract] [Full Text]  
  • Zelinskyy, G., Robertson, S. J., Schimmer, S., Messer, R. J., Hasenkrug, K. J., Dittmer, U. (2005). CD8+ T-Cell Dysfunction due to Cytolytic Granule Deficiency in Persistent Friend Retrovirus Infection. J. Virol. 79: 10619-10626 [Abstract] [Full Text]  
  • Koibuchi, T., Allen, T. M., Lichterfeld, M., Mui, S. K., O'Sullivan, K. M., Trocha, A., Kalams, S. A., Johnson, R. P., Walker, B. D. (2005). Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection. J. Virol. 79: 8171-8181 [Abstract] [Full Text]  
  • Peretz, Y., Alter, G., Boisvert, M.-P., Hatzakis, G., Tsoukas, C. M., Bernard, N. F. (2005). Human Immunodeficiency Virus (HIV)-Specific Gamma Interferon Secretion Directed against All Expressed HIV Genes: Relationship to Rate of CD4 Decline. J. Virol. 79: 4908-4917 [Abstract] [Full Text]  
  • Kim, A. Y., Lauer, G. M., Ouchi, K., Addo, M. M., Lucas, M., Wiesch, J. S. z., Timm, J., Boczanowski, M., Duncan, J. E., Wurcel, A. G., Casson, D., Chung, R. T., Draenert, R., Klenerman, P., Walker, B. D. (2005). The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1. Blood 105: 1170-1178 [Abstract] [Full Text]  
  • Timm, J., Lauer, G. M., Kavanagh, D. G., Sheridan, I., Kim, A. Y., Lucas, M., Pillay, T., Ouchi, K., Reyor, L. L., zur Wiesch, J. S., Gandhi, R. T., Chung, R. T., Bhardwaj, N., Klenerman, P., Walker, B. D., Allen, T. M. (2004). CD8 Epitope Escape and Reversion in Acute HCV Infection. JEM 200: 1593-1604 [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]  
  • Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N., Ahmed, R. (2004). Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA 101: 16004-16009 [Abstract] [Full Text]  
  • Lichterfeld, M., Kaufmann, D. E., Yu, X. G., Mui, S. K., Addo, M. M., Johnston, M. N., Cohen, D., Robbins, G. K., Pae, E., Alter, G., Wurcel, A., Stone, D., Rosenberg, E. S., Walker, B. D., Altfeld, M. (2004). Loss of HIV-1-specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1-specific CD4+ T Cells. JEM 200: 701-712 [Abstract] [Full Text]  
  • Norris, P. J., Moffett, H. F., Yang, O. O., Kaufmann, D. E., Clark, M. J., Addo, M. M., Rosenberg, E. S. (2004). Beyond Help: Direct Effector Functions of Human Immunodeficiency Virus Type 1-Specific CD4+ T Cells. J. Virol. 78: 8844-8851 [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»