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 Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaufmann, D. E. Articles by Rosenberg, E. S. Search for Related Content PubMed PubMed Citation Articles by Kaufmann, D. E. Articles by Rosenberg, E. S.

Comprehensive Analysis of Human Immunodeficiency Virus Type 1-Specific CD4 Responses Reveals Marked Immunodominance of gag and nef and the Presence of Broadly Recognized Peptides

Partners AIDS Research Center and Infectious Disease Unit,¹ Howard Hughes Medical Institute, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02114,⁴ Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,³ Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92121²

Received 11 August 2003/ Accepted 5 January 2004

Increasing evidence suggests that human immunodeficiency virus type 1 (HIV-1)-specific CD4 T-cell responses contribute to effective immune control of HIV-1 infection. However, the breadths and specificities of these responses have not been defined. We screened fresh CD8-depleted peripheral blood mononuclear cells (PBMC) from 36 subjects at different stages of HIV-1 infection for virus-specific CD4 responses by gamma interferon enzyme-linked immunospot assay, using 410 overlapping peptides spanning all HIV-1 proteins (based on the clade B consensus sequence). HIV-1-specific CD4 responses were identified in 30 of the 36 individuals studied, with the strongest and broadest responses detected in persons treated in acute infection who underwent treatment interruption. In individuals with identified responses, the total number of recognized HIV-1 peptides ranged from 1 to 36 (median, 7) and the total magnitude of responses ranged from 80 to >14,600 (median, 990) spot-forming cells/10⁶ CD8-depleted PBMC. Neither the total magnitude nor the number of responses correlated with viremia. The most frequent and robust responses were directed against epitopes within the Gag and Nef proteins. Peptides targeted by 25% of individuals were then tested for binding to a panel of common HLA-DR molecules. All bound broadly to at least four of the eight alleles tested, and two bound to all of the HLA-DR molecules studied. Fine mapping and HLA restriction of the responses against four of these peptides showed a combination of clustering of epitopes and promiscuous presentation of the same epitopes by different HLA class II alleles. These findings have implications for the design of immunotherapeutic strategies and for testing candidate HIV vaccines.

This article has been cited by other articles:

• Landry, S. J. (2008). Three-Dimensional Structure Determines the Pattern of CD4+ T-Cell Epitope Dominance in Influenza Virus Hemagglutinin. J. Virol. 82: 1238-1248 [Abstract] [Full Text]  
• Giraldo-Vela, J. P., Rudersdorf, R., Chung, C., Qi, Y., Wallace, L. T., Bimber, B., Borchardt, G. J., Fisk, D. L., Glidden, C. E., Loffredo, J. T., Piaskowski, S. M., Furlott, J. R., Morales-Martinez, J. P., Wilson, N. A., Rehrauer, W. M., Lifson, J. D., Carrington, M., Watkins, D. I. (2008). The Major Histocompatibility Complex Class II Alleles Mamu-DRB1*1003 and -DRB1*0306 Are Enriched in a Cohort of Simian Immunodeficiency Virus-Infected Rhesus Macaque Elite Controllers. J. Virol. 82: 859-870 [Abstract] [Full Text]  
• Frahm, N., Kaufmann, D. E., Yusim, K., Muldoon, M., Kesmir, C., Linde, C. H., Fischer, W., Allen, T. M., Li, B., McMahon, B. H., Faircloth, K. L., Hewitt, H. S., Mackey, E. W., Miura, T., Khatri, A., Wolinsky, S., McMichael, A., Funkhouser, R. K., Walker, B. D., Brander, C., Korber, B. T. (2007). Increased Sequence Diversity Coverage Improves Detection of HIV-Specific T Cell Responses. J. Immunol. 179: 6638-6650 [Abstract] [Full Text]  
• James, E. A., Bui, J., Berger, D., Huston, L., Roti, M., Kwok, W. W. (2007). Tetramer-guided epitope mapping reveals broad, individualized repertoires of tetanus toxin-specific CD4+ T cells and suggests HLA-based differences in epitope recognition. Int Immunol 19: 1291-1301 [Abstract] [Full Text]  
• Mothe, B. R., Stewart, B. S., Oseroff, C., Bui, H.-H., Stogiera, S., Garcia, Z., Dow, C., Rodriguez-Carreno, M. P., Kotturi, M., Pasquetto, V., Botten, J., Crotty, S., Janssen, E., Buchmeier, M. J., Sette, A. (2007). Chronic Lymphocytic Choriomeningitis Virus Infection Actively Down-Regulates CD4+ T Cell Responses Directed against a Broad Range of Epitopes. J. Immunol. 179: 1058-1067 [Abstract] [Full Text]  
• Willberg, C. B., Pillai, S. K., Sharp, E. R., Rosenberg, M. G., Agudelo, J. D., Barbour, J. D., Nixon, D. F. (2007). Rational Peptide Selection To Detect Human Immunodeficiency Virus Type 1-Specific T-Cell Responses under Resource-Limited Conditions. CVI 14: 785-788 [Abstract] [Full Text]  
• Moutaftsi, M., Bui, H.-H., Peters, B., Sidney, J., Salek-Ardakani, S., Oseroff, C., Pasquetto, V., Crotty, S., Croft, M., Lefkowitz, E. J., Grey, H., Sette, A. (2007). Vaccinia Virus-Specific CD4+ T Cell Responses Target a Set of Antigens Largely Distinct from Those Targeted by CD8+ T Cell Responses. J. Immunol. 178: 6814-6820 [Abstract] [Full Text]  
• Younes, S.-A., Trautmann, L., Yassine-Diab, B., Kalfayan, L. H., Kernaleguen, A.-E., Cameron, T. O., Boulassel, R., Stern, L. J., Routy, J.-P., Grossman, Z., Dumont, A. R., Sekaly, R.-P. (2007). The Duration of Exposure to HIV Modulates the Breadth and the Magnitude of HIV-Specific Memory CD4+ T Cells. J. Immunol. 178: 788-797 [Abstract] [Full Text]  
• Gauduin, M.-C., Yu, Y., Barabasz, A., Carville, A., Piatak, M., Lifson, J. D., Desrosiers, R. C., Johnson, R. P. (2006). Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection. J. Exp. Med. 203: 2661-2672 [Abstract] [Full Text]  
• Dunham, R., Pagliardini, P., Gordon, S., Sumpter, B., Engram, J., Moanna, A., Paiardini, M., Mandl, J. N., Lawson, B., Garg, S., McClure, H. M., Xu, Y.-X., Ibegbu, C., Easley, K., Katz, N., Pandrea, I., Apetrei, C., Sodora, D. L., Staprans, S. I., Feinberg, M. B., Silvestri, G. (2006). The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108: 209-217 [Abstract] [Full Text]  
• Dorrell, L., Yang, H., Ondondo, B., Dong, T., di Gleria, K., Suttill, A., Conlon, C., Brown, D., Williams, P., Bowness, P., Goonetilleke, N., Rostron, T., Rowland-Jones, S., Hanke, T., McMichael, A. (2006). Expansion and Diversification of Virus-Specific T Cells following Immunization of Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals with a Recombinant Modified Vaccinia Virus Ankara/HIV-1 Gag Vaccine.. J. Virol. 80: 4705-4716 [Abstract] [Full Text]  
• Goonetilleke, N., Moore, S., Dally, L., Winstone, N., Cebere, I., Mahmoud, A., Pinheiro, S., Gillespie, G., Brown, D., Loach, V., Roberts, J., Guimaraes-Walker, A., Hayes, P., Loughran, K., Smith, C., De Bont, J., Verlinde, C., Vooijs, D., Schmidt, C., Boaz, M., Gilmour, J., Fast, P., Dorrell, L., Hanke, T., McMichael, A. J. (2006). Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8+ T-Cell Epitopes.. J. Virol. 80: 4717-4728 [Abstract] [Full Text]  
• Cohen, W. M., Pouvelle-Moratille, S., Wang, X.-F., Farci, S., Munier, G., Charron, D., Menez, A., Busson, M., Maillere, B. (2006). Scanning the HIV Genome for CD4+ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule. J. Immunol. 176: 5401-5408 [Abstract] [Full Text]  
• Wang, Z., Metcalf, B., Ribeiro, R. M., McClure, H., Kaur, A. (2006). Th-1-Type Cytotoxic CD8+ T-Lymphocyte Responses to Simian Immunodeficiency Virus (SIV) Are a Consistent Feature of Natural SIV Infection in Sooty Mangabeys. J. Virol. 80: 2771-2783 [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]  
• Burgers, W. A., van Harmelen, J. H., Shephard, E., Adams, C., Mgwebi, T., Bourn, W., Hanke, T., Williamson, A.-L., Williamson, C. (2006). Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial. J. Gen. Virol. 87: 399-410 [Abstract] [Full Text]  
• Seth, N., Kaufmann, D., Lahey, T., Rosenberg, E. S., Wucherpfennig, K. W. (2005). Expansion and Contraction of HIV-Specific CD4 T Cells with Short Bursts of Viremia, but Physical Loss of the Majority of These Cells with Sustained Viral Replication. J. Immunol. 175: 6948-6958 [Abstract] [Full Text]  
• Woodberry, T., Suscovich, T. J., Henry, L. M., August, M., Waring, M. T., Kaur, A., Hess, C., Kutok, J. L., Aster, J. C., Wang, F., Scadden, D. T., Brander, C. (2005). {alpha}E{beta}7 (CD103) Expression Identifies a Highly Active, Tonsil-Resident Effector-Memory CTL Population. J. Immunol. 175: 4355-4362 [Abstract] [Full Text]  
• Schulze zur Wiesch, J., Lauer, G. M., Day, C. L., Kim, A. Y., Ouchi, K., Duncan, J. E., Wurcel, A. G., Timm, J., Jones, A. M., Mothe, B., Allen, T. M., McGovern, B., Lewis-Ximenez, L., Sidney, J., Sette, A., Chung, R. T., Walker, B. D. (2005). Broad Repertoire of the CD4+ Th Cell Response in Spontaneously Controlled Hepatitis C Virus Infection Includes Dominant and Highly Promiscuous Epitopes. J. Immunol. 175: 3603-3613 [Abstract] [Full Text]  
• Zaunders, J. J., Munier, M. L., Kaufmann, D. E., Ip, S., Grey, P., Smith, D., Ramacciotti, T., Quan, D., Finlayson, R., Kaldor, J., Rosenberg, E. S., Walker, B. D., Cooper, D. A., Kelleher, A. D., on behalf of the PHAEDRA Study Team, (2005). Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection. Blood 106: 1660-1667 [Abstract] [Full Text]  
• Joos, B., Trkola, A., Fischer, M., Kuster, H., Rusert, P., Leemann, C., Boni, J., Oxenius, A., Price, D. A., Phillips, R. E., Wong, J. K., Hirschel, B., Weber, R., Gunthard, H. F., the Swiss HIV Cohort Study, (2005). Low Human Immunodeficiency Virus Envelope Diversity Correlates with Low In Vitro Replication Capacity and Predicts Spontaneous Control of Plasma Viremia after Treatment Interruptions. J. Virol. 79: 9026-9037 [Abstract] [Full Text]