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 Barouch, D. H. Articles by Letvin, N. L. Search for Related Content PubMed PubMed Citation Articles by Barouch, D. H. Articles by Letvin, N. L.

Viral Escape from Dominant Simian Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes in DNA-Vaccinated Rhesus Monkeys

Dan H. Barouch,^1* Jennifer Kunstman,² Jennifer Glowczwskie,² Kevin J. Kunstman,² Michael A. Egan,^1, Fred W. Peyerl,¹ Sampa Santra,¹ Marcelo J. Kuroda,¹ Jörn E. Schmitz,¹ Kristin Beaudry,¹ Georgia R. Krivulka,¹ Michelle A. Lifton,¹ Darci A. Gorgone,¹ Steven M. Wolinsky,² and Norman L. Letvin¹

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,¹ Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611²

Received 31 January 2003/ Accepted 1 April 2003

Virus-specific cytotoxic T lymphocytes (CTL) are critical for control of human immunodeficiency virus type 1 replication. However, viral escape from CTL recognition can undermine this immune control. Here we demonstrate the high frequency and pattern of viral escape from dominant epitope-specific CTL in SIV gag DNA-vaccinated rhesus monkeys following a heterologous simian immunodeficiency virus (SIV) challenge. DNA-vaccinated monkeys exhibited initial effective control of the SIV challenge, but this early control was lost by serial breakthroughs of viral replication over a 3-year follow-up period. Increases in plasma viral RNA correlated temporally with declines of dominant SIV epitope-specific CD8⁺ T-lymphocyte responses and the emergence of viral mutations that escaped recognition by dominant epitope-specific CTL. Viral escape from CTL occurred in a total of seven of nine vaccinated and control monkeys, including three animals that initially controlled viral replication to undetectable levels of plasma viral RNA. These data suggest that CTL exert selective pressure on viral replication and that viral escape from CTL may be a limitation of CTL-based AIDS vaccine strategies.

Present address: Department of Viral Vaccine Immunology, Wyeth Research, Pearl River, NY 10965.

This article has been cited by other articles:

• Smith, M. Z., Asher, T. E., Venturi, V., Davenport, M. P., Douek, D. C., Price, D. A., Kent, S. J. (2008). Limited Maintenance of Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 T-Cell Receptor Clonotypes after Virus Challenge. J. Virol. 82: 7357-7368 [Abstract] [Full Text]  
• Rousseau, C. M., Daniels, M. G., Carlson, J. M., Kadie, C., Crawford, H., Prendergast, A., Matthews, P., Payne, R., Rolland, M., Raugi, D. N., Maust, B. S., Learn, G. H., Nickle, D. C., Coovadia, H., Ndung'u, T., Frahm, N., Brander, C., Walker, B. D., Goulder, P. J. R., Bhattacharya, T., Heckerman, D. E., Korber, B. T., Mullins, J. I. (2008). HLA Class I-Driven Evolution of Human Immunodeficiency Virus Type 1 Subtype C Proteome: Immune Escape and Viral Load. J. Virol. 82: 6434-6446 [Abstract] [Full Text]  
• Kim, E.-Y., Veazey, R. S., Zahn, R., McEvers, K. J., Baumeister, S. H. C., Foster, G. J., Rett, M. D., Newberg, M. H., Kuroda, M. J., Rieber, E. P., Piatak, M. Jr., Lifson, J. D., Letvin, N. L., Wolinsky, S. M., Schmitz, J. E. (2008). Contribution of CD8+ T Cells to Containment of Viral Replication and Emergence of Mutations in Mamu-A*01-Restricted Epitopes in Simian Immunodeficiency Virus-Infected Rhesus Monkeys. J. Virol. 82: 5631-5635 [Abstract] [Full Text]  
• Sadagopal, S., Amara, R. R., Kannanganat, S., Sharma, S., Chennareddi, L., Robinson, H. L. (2008). Expansion and Exhaustion of T-Cell Responses during Mutational Escape from Long-Term Viral Control in Two DNA/Modified Vaccinia Virus Ankara-Vaccinated and Simian-Human Immunodeficiency Virus SHIV-89.6P-Challenged Macaques. J. Virol. 82: 4149-4153 [Abstract] [Full Text]  
• Sen, P., Charini, W. A., Subbramanian, R. A., Manuel, E. R., Kuroda, M. J., Autissier, P. A., Letvin, N. L. (2008). Clonal Focusing of Epitope-Specific CD8+ T Lymphocytes in Rhesus Monkeys following Vaccination and Simian-Human Immunodeficiency Virus Challenge. J. Virol. 82: 805-816 [Abstract] [Full Text]  
• Fujiwara, M., Tanuma, J., Koizumi, H., Kawashima, Y., Honda, K., Mastuoka-Aizawa, S., Dohki, S., Oka, S., Takiguchi, M. (2008). Different Abilities of Escape Mutant-Specific Cytotoxic T Cells To Suppress Replication of Escape Mutant and Wild-Type Human Immunodeficiency Virus Type 1 in New Hosts. J. Virol. 82: 138-147 [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]  
• Mueller, Y. M., Petrovas, C., Do, D. H., Altork, S. R., Fischer-Smith, T., Rappaport, J., Altman, J. D., Lewis, M. G., Katsikis, P. D. (2007). Early Establishment and Antigen Dependence of Simian Immunodeficiency Virus-Specific CD8+ T-Cell Defects. J. Virol. 81: 10861-10868 [Abstract] [Full Text]  
• Buonaguro, L., Tornesello, M. L., Buonaguro, F. M. (2007). Human Immunodeficiency Virus Type 1 Subtype Distribution in the Worldwide Epidemic: Pathogenetic and Therapeutic Implications. J. Virol. 81: 10209-10219 [Full Text]  
• Asquith, B., McLean, A. R. (2007). In vivo CD8+ T cell control of immunodeficiency virus infection in humans and macaques. Proc. Natl. Acad. Sci. USA 104: 6365-6370 [Abstract] [Full Text]  
• Loffredo, J. T., Burwitz, B. J., Rakasz, E. G., Spencer, S. P., Stephany, J. J., Giraldo Vela, J. P., Martin, S. R., Reed, J., Piaskowski, S. M., Furlott, J., Weisgrau, K. L., Rodrigues, D. S., Soma, T., Napoe, G., Friedrich, T. C., Wilson, N. A., Kallas, E. G., Watkins, D. I. (2007). The Antiviral Efficacy of Simian Immunodeficiency Virus-Specific CD8+ T Cells Is Unrelated to Epitope Specificity and Is Abrogated by Viral Escape. J. Virol. 81: 2624-2634 [Abstract] [Full Text]  
• De Boer, R. J. (2007). Understanding the Failure of CD8+ T-Cell Vaccination against Simian/Human Immunodeficiency Virus. J. Virol. 81: 2838-2848 [Abstract] [Full Text]  
• Chung, C., Lee, W., Loffredo, J. T., Burwitz, B., Friedrich, T. C., Giraldo Vela, J. P., Napoe, G., Rakasz, E. G., Wilson, N. A., Allison, D. B., Watkins, D. I. (2007). Not All Cytokine-Producing CD8+ T Cells Suppress Simian Immunodeficiency Virus Replication. J. Virol. 81: 1517-1523 [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]  
• 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]  
• Kawada, M., Igarashi, H., Takeda, A., Tsukamoto, T., Yamamoto, H., Dohki, S., Takiguchi, M., Matano, T. (2006). Involvement of Multiple Epitope-Specific Cytotoxic T-Lymphocyte Responses in Vaccine-Based Control of Simian Immunodeficiency Virus Replication in Rhesus Macaques. J. Virol. 80: 1949-1958 [Abstract] [Full Text]  
• Barratt-Boyes, S. M., Soloff, A. C., Gao, W., Nwanegbo, E., Liu, X., Rajakumar, P. A., Brown, K. N., Robbins, P. D., Murphey-Corb, M., Day, R. D., Gambotto, A. (2006). Broad cellular immunity with robust memory responses to simian immunodeficiency virus following serial vaccination with adenovirus 5- and 35-based vectors. J. Gen. Virol. 87: 139-149 [Abstract] [Full Text]  
• Newberg, M. H., McEvers, K. J., Gorgone, D. A., Lifton, M. A., Baumeister, S. H. C., Veazey, R. S., Schmitz, J. E., Letvin, N. L. (2006). Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys. J. Immunol. 176: 319-328 [Abstract] [Full Text]  
• McDermott, A. B., O'Connor, D. H., Fuenger, S., Piaskowski, S., Martin, S., Loffredo, J., Reynolds, M., Reed, J., Furlott, J., Jacoby, T., Riek, C., Dodds, E., Krebs, K., Davies, M.-E., Schleif, W. A., Casimiro, D. R., Shiver, J. W., Watkins, D. I. (2005). Cytotoxic T-Lymphocyte Escape Does Not Always Explain the Transient Control of Simian Immunodeficiency Virus SIVmac239 Viremia in Adenovirus-Boosted and DNA-Primed Mamu-A*01-Positive Rhesus Macaques. J. Virol. 79: 15556-15566 [Abstract] [Full Text]  
• Loffredo, J. T., Rakasz, E. G., Giraldo, J. P., Spencer, S. P., Grafton, K. K., Martin, S. R., Napoe, G., Yant, L. J., Wilson, N. A., Watkins, D. I. (2005). Tat28-35SL8-Specific CD8+ T Lymphocytes Are More Effective than Gag181-189CM9-Specific CD8+ T Lymphocytes at Suppressing Simian Immunodeficiency Virus Replication in a Functional In Vitro Assay. J. Virol. 79: 14986-14991 [Abstract] [Full Text]  
• Milicic, A., Edwards, C. T. T., Hue, S., Fox, J., Brown, H., Pillay, T., Drijfhout, J. W., Weber, J. N., Holmes, E. C., Fidler, S. J., Zhang, H.-T., Phillips, R. E. (2005). Sexual Transmission of Single Human Immunodeficiency Virus Type 1 Virions Encoding Highly Polymorphic Multisite Cytotoxic T-Lymphocyte Escape Variants. J. Virol. 79: 13953-13962 [Abstract] [Full Text]  
• Sanchez-Merino, V., Nie, S., Luzuriaga, K. (2005). HIV-1-Specific CD8+ T Cell Responses and Viral Evolution in Women and Infants. J. Immunol. 175: 6976-6986 [Abstract] [Full Text]  
• Peyerl, F. W., Barouch, D. H., Bazick, H. S., Manuel, E., Letvin, N. L. (2005). Use of Molecular Beacons for Rapid, Real-Time, Quantitative Monitoring of Cytotoxic T-Lymphocyte Epitope Mutations in Simian Immunodeficiency Virus. J. Clin. Microbiol. 43: 4773-4779 [Abstract] [Full Text]  
• Geels, M. J., Dubey, S. A., Anderson, K., Baan, E., Bakker, M., Pollakis, G., Paxton, W. A., Shiver, J. W., Goudsmit, J. (2005). Broad Cross-Clade T-Cell Responses to Gag in Individuals Infected with Human Immunodeficiency Virus Type 1 Non-B Clades (A to G): Importance of HLA Anchor Residue Conservation. J. Virol. 79: 11247-11258 [Abstract] [Full Text]  
• MacNamara, K. C., Chua, M. M., Phillips, J. J., Weiss, S. R. (2005). Contributions of the Viral Genetic Background and a Single Amino Acid Substitution in an Immunodominant CD8+ T-Cell Epitope to Murine Coronavirus Neurovirulence. J. Virol. 79: 9108-9118 [Abstract] [Full Text]  
• Gilbert, P. B., Sun, Y. (2005). Failure time analysis of HIV vaccine effects on viral load and antiretroviral therapy initiation. Biostatistics 6: 374-394 [Abstract] [Full Text]  
• Sadagopal, S., Amara, R. R., Montefiori, D. C., Wyatt, L. S., Staprans, S. I., Kozyr, N. L., McClure, H. M., Moss, B., Robinson, H. L. (2005). Signature for Long-Term Vaccine-Mediated Control of a Simian and Human Immunodeficiency Virus 89.6P Challenge: Stable Low-Breadth and Low-Frequency T-Cell Response Capable of Coproducing Gamma Interferon and Interleukin-2. J. Virol. 79: 3243-3253 [Abstract] [Full Text]  
• Smith, M. Z., Dale, C. J., De Rose, R., Stratov, I., Fernandez, C. S., Brooks, A. G., Weinfurter, J., Krebs, K., Riek, C., Watkins, D. I., O'Connor, D. H., Kent, S. J. (2005). Analysis of Pigtail Macaque Major Histocompatibility Complex Class I Molecules Presenting Immunodominant Simian Immunodeficiency Virus Epitopes. J. Virol. 79: 684-695 [Abstract] [Full Text]  
• McKenna, P. M., Aye, P. P., Dietzschold, B., Montefiori, D. C., Martin, L. N., Marx, P. A., Pomerantz, R. J., Lackner, A., Schnell, M. J. (2004). Immunogenicity Study of Glycoprotein-Deficient Rabies Virus Expressing Simian/Human Immunodeficiency Virus SHIV89.6P Envelope in a Rhesus Macaque. J. Virol. 78: 13455-13459 [Abstract] [Full Text]  
• Peyerl, F. W., Bazick, H. S., Newberg, M. H., Barouch, D. H., Sodroski, J., Letvin, N. L. (2004). Fitness Costs Limit Viral Escape from Cytotoxic T Lymphocytes at a Structurally Constrained Epitope. J. Virol. 78: 13901-13910 [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]  
• Davenport, M. P., Ribeiro, R. M., Chao, D. L., Perelson, A. S. (2004). Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus. J. Virol. 78: 11340-11351 [Abstract] [Full Text]  
• Loffredo, J. T., Sidney, J., Wojewoda, C., Dodds, E., Reynolds, M. R., Napoe, G., Mothe, B. R., O'Connor, D. H., Wilson, N. A., Watkins, D. I., Sette, A. (2004). Identification of Seventeen New Simian Immunodeficiency Virus-Derived CD8+ T Cell Epitopes Restricted by the High Frequency Molecule, Mamu-A*02, and Potential Escape from CTL Recognition. J. Immunol. 173: 5064-5076 [Abstract] [Full Text]  
• Makitalo, B., Lundholm, P., Hinkula, J., Nilsson, C., Karlen, K., Morner, A., Sutter, G., Erfle, V., Heeney, J. L., Wahren, B., Biberfeld, G., Thorstensson, R. (2004). Enhanced cellular immunity and systemic control of SHIV infection by combined parenteral and mucosal administration of a DNA prime MVA boost vaccine regimen. J. Gen. Virol. 85: 2407-2419 [Abstract] [Full Text]  
• Reyes-Sandoval, A., Fitzgerald, J. C., Grant, R., Roy, S., Xiang, Z. Q., Li, Y., Gao, G. P., Wilson, J. M., Ertl, H. C. J. (2004). Human Immunodeficiency Virus Type 1-Specific Immune Responses in Primates upon Sequential Immunization with Adenoviral Vaccine Carriers of Human and Simian Serotypes. J. Virol. 78: 7392-7399 [Abstract] [Full Text]  
• Hirsch, V. M., Santra, S., Goldstein, S., Plishka, R., Buckler-White, A., Seth, A., Ourmanov, I., Brown, C. R., Engle, R., Montefiori, D., Glowczwskie, J., Kunstman, K., Wolinsky, S., Letvin, N. L. (2004). Immune Failure in the Absence of Profound CD4+ T-Lymphocyte Depletion in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques. J. Virol. 78: 275-284 [Abstract] [Full Text]  
• Peyerl, F. W., Barouch, D. H., Yeh, W. W., Bazick, H. S., Kunstman, J., Kunstman, K. J., Wolinsky, S. M., Letvin, N. L. (2003). Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope. J. Virol. 77: 12572-12578 [Abstract] [Full Text]  
• Smith, S. M., Pentlicky, S., Klase, Z., Singh, M., Neuveut, C., Lu, C.-y., Reitz, M. S. Jr., Yarchoan, R., Marx, P. A., Jeang, K.-T. (2003). An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection. J. Biol. Chem. 278: 44816-44825 [Abstract] [Full Text]  
• Doria-Rose, N. A., Ohlen, C., Polacino, P., Pierce, C. C., Hensel, M. T., Kuller, L., Mulvania, T., Anderson, D., Greenberg, P. D., Hu, S.-L., Haigwood, N. L. (2003). Multigene DNA Priming-Boosting Vaccines Protect Macaques from Acute CD4+-T-Cell Depletion after Simian-Human Immunodeficiency Virus SHIV89.6P Mucosal Challenge. J. Virol. 77: 11563-11577 [Abstract] [Full Text]