Unique Acquisition of Cytotoxic T-Lymphocyte Escap
http://www.100md.com
病菌学杂志 2005年第18期
The Peter Medawar Building for Pathogen Research and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
Department of Immunohaematology, Leiden University Medical Centre, Leiden, The Netherlands
Nelson R. Mandela Medical School, Department of Obstetrics and Gynaecology, University of Natal, Durban, South Africa
Nelson R. Mandela Medical School, Department of Paediatrics and Infant Health, University of Natal, Durban, South Africa
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Queen Elizabeth Hospital, Bridgetown, Barbados
Department of Evolutionary Biology, University of Oxford, Oxford, United Kingdom
Centre for HIV and AIDS Networking, University of Natal, Durban, South Africa
ABSTRACT
The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.
TEXT
In developing countries, one-third of human immunodeficiency virus type 1 (HIV-1)-infected children have rapidly progressive disease and die in infancy (23). It is unknown why infants have particularly poor control of HIV-1 (5, 6, 8, 9). Cytotoxic T-lymphocyte (CTL) responses can control adult HIV-1 and simian immunodeficiency virus infections (12, 18, 20) but select for CTL escape mutations with a subsequent loss of immune control (2, 11, 14, 19). Few studies have described CTL in early perinatal HIV-1 (3, 17). However, it is unclear whether rapid progression in infants occurs in association with an undetectable HIV-specific CTL response or with an ineffective HIV-specific CTL response (21). This distinction is of relevance to pediatric HIV vaccine design strategies. Here we provide evidence that very early in the first year of life, CTL drive the selection of de novo escape variants, which together with mother-to-child transmission of viruses preadapted to the HLA class I alleles expressed in the infant, are likely to contribute to a lack of immune control in pediatric infection.
We studied five rapidly progressing infants and their mothers from Durban, South Africa, from pregnancy to up to 1.5 years after birth (see Table S1 in the supplemental material). Three of the five infants died with HIV-1 disease within 3 to 23 months. A fourth infant commenced antiretroviral therapy at 1 year of age after the onset of AIDS. The fifth infant was withdrawn from the study by his guardians following the AIDS-related death of his mother.
To assess infant immunity-driven viral evolution, we examined HIV-1 viral genes encoding the most immunogenic viral proteins (1), Gag and Nef. gag and nef were sequenced from plasma RNAs collected from infants and mothers from pregnancy onwards. Phylogenetic analysis (22) confirmed the relatedness of clones from mother-child pairs, all of which clustered with clade C viruses (see Fig. S1 in the supplemental material).
At six epitopes from three infants, we identified de novo CTL escape (Table 1; see Table S2 in the supplemental material). Using the method of CODEML selection analysis as previously described (7), four of these antigenic sites were shown to be under positive selection in these infants (Table 1) (dn/ds > 1; P < 0.05). Maximum likelihood phylogenetic analysis indicated that in each case, the CTL escape variant had evolved subsequently in the infant (Fig. 1 and data not shown). No variation was observed at these sites in >50 clones from each mother sampled across different time points. This observation, together with phylogenetic evidence, suggests that the CTL escape viruses had arisen in the infants.
We next examined epitopes presented by alleles shared by mother and child to determine whether escape variants could be specifically selected in rapidly progressing infants. An analysis of nef from infant I4 demonstrated the selection of a Pro-to-Ser or -Gln change at position 2 of the HLA-B4201 epitope, TPGPGVRYPL, between 10 and 26 weeks postpartum (Table 1; Fig. 2a). These variant peptides generated specifically in the infant were not recognized (Fig. 2b) and did not bind to HLA-B4201 (Fig. 2c). These CTL escape mutants driven by selection pressure in the infant were absent from the B4201-positive mother, in spite of the presence of the same TL10-specific CTL response in the mother (Fig. 2d). The combination of a consistent high-frequency TL10-specific response and a persistent high maternal viral load of >100,000 HIV RNA copies/ml of plasma suggests that this particular response was ineffective (4, 24), whereas the same response in the infant "drove" the evolution of the escape variants early on in the infection. These data demonstrate that, at least for certain epitopes, selection for escape may operate during early pediatric HIV infection but may be absent from chronic adult infections.
It has previously been shown that children may be in a particularly disadvantaged position with respect to the epitopes available for an effective HIV-specific CTL response as a result of mother-to-child transmission of a virus that has adapted successfully to the maternal class I alleles (10, 15). Since infants typically share 50% of their HLA class I alleles with their mothers, it might be predicted that the remaining 50% of the infant's HLA alleles that are paternally inherited could be utilized more successfully to mount responses against maternally transmitted virus. However, in some cases, the maternal HIV infection may result from the transmission of virus from the child's father. To examine the question of whether viruses adapted to paternal HLA alleles may in this way be indirectly transmitted to the child via the mother, we sought "footprints" of paternal HLA alleles in viruses transmitted from mother to child. Previous studies of gag sequences from HLA-B57-positive subjects have identified "footprints" of HLA-B57 which persist following transmission to B57-negative subjects (16). In particular, these arise at Gag residues 219 (H219Q) and 248. For clade B infections, the characteristic B57 footprint is G248A, whereas for clade C infections, the B57 footprint at this site is A248T (P = 0.036) (16). The occurrence of such HLA-B57-associated polymorphisms in the HLA-B57-negative mother M5 (Fig. 3a) is thus indicative of the transmission of virus from an HLA-B57-positive subject to the mother (P = 0.008) (16). Since child I5 had HLA-B57, one may speculate that the HLA-B57-positive father in this instance directly transmitted a virus carrying these HLA-B57-associated mutations to the HLA-B57-negative mother, M5. These B57 "footprints" persisting in the mother were, in turn, transmitted to the HLA-B57-positive child. In this example, the transmitted variant A248T did not affect binding to HLA-B57, and thus a TW10 response (and further immune pressure on the virus) could be generated by the child. The transmission of an escape variant unable to bind to the HLA molecule would have precluded a response in the infant. One example of mother-to-child transmission of such a variant has been described for the B27-KK10 epitope, where Arg is required for binding to B27 (10, 11). We identified another example of this in a Barbadian mother-child pair (Fig. 3b), but with HLA-B27 being shared by the mother and child. In this instance, the presence of the B27 footprint R264X in the virus of the B27-negative father and a sequence analysis demonstrating the shared phylogeny of the paternal and maternal viruses (Fig. 3c) indicated that in this case, transmission of the virus occurred from mother to father. Analyses of these and other families show that HIV infection in one parent not infrequently is the result of transmission by the other parent (Fig. 3c), and thus the acquisition of a virus adapted to paternal and maternal HLA alleles may occur in the infant via mother-to-child transmission.
These data show that there are several unique influences that may compromise the effectiveness of the early pediatric HIV-specific immune response that involve CTL escape. These include the transmission of escape variants generated in the mother and also those originally generated in the father and the early development of escape mutations in epitopes at which selection for escape does not necessarily occur in adult infections. The occurrence of de novo escape during early pediatric infections implies, on the one hand, a suboptimal immune response akin to the development of drug-resistant mutations in the presence of suboptimal antiretroviral therapy. On the other hand, the presence of functional CTL generated against HIV in early infancy suggests the possibility that early immunomodulatory interventions may have promise to improve the efficacy of these CTL responses and bring about more successful HIV-specific control of pediatric infections in the future.
Supplemental material for this article may be found at http://jvi.asm.org/.
REFERENCES
Addo, M. M., X. G. Yu, A. Rathod, D. Cohen, R. L. Eldridge, D. Strick, M. N. Johnston, C. Corcoran, A. G. Wurcel, C. A. Fitzpatrick, M. E. Feeney, W. R. Rodriguez, N. Basgoz, R. Draenert, D. R. Stone, C. Brander, P. J. Goulder, E. S. Rosenberg, M. Altfeld, and B. D. Walker. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77:2081-2092.
Barouch, D. H., J. Kunstman, M. J. Kuroda, J. E. Schmitz, S. Santra, F. W. Peyerl, G. R. Krivulka, K. Beaudry, M. A. Lifton, D. A. Gorgone, D. C. Montefiori, M. G. Lewis, S. M. Wolinsky, and N. L. Letvin. 2002. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335-339.
Brander, C., P. J. Goulder, K. Luzuriaga, O. O. Yang, K. E. Hartman, N. G. Jones, B. D. Walker, and S. A. Kalams. 1999. Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection. J. Immunol. 162:4796-4800.
Buseyne, F., S. Blanche, D. Schmitt, C. Griscelli, and Y. Riviere. 1993. Detection of HIV-specific cell-mediated cytotoxicity in the peripheral blood from infected children. J. Immunol. 150:3569-3581.
Buseyne, F., M. Burgard, J. P. Teglas, E. Bui, C. Rouzioux, M. J. Mayaux, S. Blanche, and Y. Riviere. 1998. Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers. AIDS Res. Hum. Retrovir. 14:1435-1444.
Cheynier, R., P. Langlade-Demoyen, M. R. Marescot, S. Blanche, G. Blondin, S. Wain-Hobson, C. Griscelli, E. Vilmer, and F. Plata. 1992. Cytotoxic T lymphocyte responses in the peripheral blood of children born to human immunodeficiency virus-1-infected mothers. Eur. J. Immunol. 22:2211-2217.
Draenert, R., S. Le Gall, K. J. Pfafferott, A. J. Leslie, P. Chetty, C. Brander, E. C. Holmes, S. C. Chang, M. E. Feeney, M. M. Addo, L. Ruiz, D. Ramduth, P. Jeena, M. Altfeld, S. Thomas, Y. Tang, C. L. Verrill, C. Dixon, J. G. Prado, P. Kiepiela, J. Martinez-Picado, B. D. Walker, and P. J. Goulder. 2004. Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J. Exp. Med. 199:905-915.
Feeney, M. E., Y. Tang, K. A. Roosevelt, A. J. Leslie, K. McIntosh, N. Karthas, B. D. Walker, and P. J. Goulder. 2004. Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J. Virol. 78:8927-8930.
Gallagher, K., M. Gorre, N. Harawa, M. Dillon, D. Wafer, E. R. Stiehm, Y. Bryson, D. Song, R. Dickover, and S. Plaeger. 1997. Timing of lymphocyte activation in neonates infected with human immunodeficiency virus. Clin. Diagn. Lab. Immunol. 4:742-747.
Goulder, P. J., C. Brander, Y. Tang, C. Tremblay, R. A. Colbert, M. M. Addo, E. S. Rosenberg, T. Nguyen, R. Allen, A. Trocha, M. Altfeld, S. He, M. Bunce, R. Funkhouser, S. I. Pelton, S. K. Burchett, K. McIntosh, B. T. Korber, and B. D. Walker. 2001. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412:334-338.
Goulder, P. J., R. E. Phillips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, and S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212-217.
Jin, X., D. E. Bauer, S. E. Tuttleton, S. Lewin, A. Gettie, J. Blanchard, C. E. Irwin, J. T. Safrit, J. Mittler, L. Weinberger, L. G. Kostrikis, L. Zhang, A. S. Perelson, and D. D. Ho. 1999. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189:991-998.
Kessler, J. H., B. Mommaas, T. Mutis, I. Huijbers, D. Vissers, W. E. Benckhuijsen, G. M. Schreuder, R. Offringa, E. Goulmy, C. J. Melief, S. H. van der Burg, and J. W. Drijfhout. 2003. Competition-based cellular peptide binding assays for 13 prevalent HLA class I alleles using fluorescein-labeled synthetic peptides. Hum. Immunol. 64:245-255.
Koenig, S., A. J. Conley, Y. A. Brewah, G. M. Jones, S. Leath, L. J. Boots, V. Davey, G. Pantaleo, J. F. Demarest, C. Carter, et al. 1995. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat. Med. 1:330-336.
Kuhn, L., E. J. Abrams, P. Palumbo, M. Bulterys, R. Aga, L. Louie, and T. Hodge. 2004. Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression. AIDS 18:1281-1289.
Leslie, A. J., K. J. Pfafferott, P. Chetty, R. Draenert, M. M. Addo, M. Feeney, Y. Tang, E. C. Holmes, T. Allen, J. G. Prado, M. Altfeld, C. Brander, C. Dixon, D. Ramduth, P. Jeena, S. A. Thomas, A. St. John, T. A. Roach, B. Kupfer, G. Luzzi, A. Edwards, G. Taylor, H. Lyall, G. Tudor-Williams, V. Novelli, J. Martinez-Picado, P. Kiepiela, B. D. Walker, and P. J. Goulder. 2004. HIV evolution: CTL escape mutation and reversion after transmission. Nat. Med. 10:282-289.
Luzuriaga, K., D. Holmes, A. Hereema, J. Wong, D. L. Panicali, and J. L. Sullivan. 1995. HIV-1-specific cytotoxic T lymphocyte responses in the first year of life. J. Immunol. 154:433-443.
McMichael, A. J., and S. L. Rowland-Jones. 2001. Cellular immune responses to HIV. Nature 410:980-987.
Peyerl, F. W., D. H. Barouch, W. W. Yeh, H. S. Bazick, J. Kunstman, K. J. Kunstman, S. M. Wolinsky, and N. L. Letvin. 2003. Simian-human immunodeficiency virus escape from cytotoxic T-lymphocyte recognition at a structurally constrained epitope. J. Virol. 77:12572-12578.
Schmitz, J. E., M. J. Kuroda, S. Santra, V. G. Sasseville, M. A. Simon, M. A. Lifton, P. Racz, K. Tenner-Racz, M. Dalesandro, B. J. Scallon, J. Ghrayeb, M. A. Forman, D. C. Montefiori, E. P. Rieber, N. L. Letvin, and K. A. Reimann. 1999. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857-860.
Scott-Algara, D., F. Buseyne, F. Porrot, B. Corre, N. Bellal, C. Rouzioux, S. Blanche, and Y. Riviere. 2005. Not all tetramer binding CD8(+) T cells can produce cytokines and chemokines involved in the effector functions of virus-specific CD8(+) T lymphocytes in HIV-1 infected children. J. Clin. Immunol. 25:57-67.
Swofford, D. L. 2003. PAUP. Phylogenetic analysis using parsimony (and other methods), version 4. Sinauer Associates, Sunderland, Mass.
Tudor-Williams, G. 2000. HIV infection in children in developing countries. Trans. R. Soc. Trop. Med. Hyg. 94:3-4.
Zafiropoulos, A., E. Barnes, C. Piggott, and P. Klenerman. 2004. Analysis of "driver" and "passenger" CD8+ T-cell responses against variable viruses. Proc. R. Soc. Lond. B Biol. Sci. 271(Suppl. 3):S53-S56.(Thillagavathie Pillay, Hu)
Department of Immunohaematology, Leiden University Medical Centre, Leiden, The Netherlands
Nelson R. Mandela Medical School, Department of Obstetrics and Gynaecology, University of Natal, Durban, South Africa
Nelson R. Mandela Medical School, Department of Paediatrics and Infant Health, University of Natal, Durban, South Africa
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Queen Elizabeth Hospital, Bridgetown, Barbados
Department of Evolutionary Biology, University of Oxford, Oxford, United Kingdom
Centre for HIV and AIDS Networking, University of Natal, Durban, South Africa
ABSTRACT
The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.
TEXT
In developing countries, one-third of human immunodeficiency virus type 1 (HIV-1)-infected children have rapidly progressive disease and die in infancy (23). It is unknown why infants have particularly poor control of HIV-1 (5, 6, 8, 9). Cytotoxic T-lymphocyte (CTL) responses can control adult HIV-1 and simian immunodeficiency virus infections (12, 18, 20) but select for CTL escape mutations with a subsequent loss of immune control (2, 11, 14, 19). Few studies have described CTL in early perinatal HIV-1 (3, 17). However, it is unclear whether rapid progression in infants occurs in association with an undetectable HIV-specific CTL response or with an ineffective HIV-specific CTL response (21). This distinction is of relevance to pediatric HIV vaccine design strategies. Here we provide evidence that very early in the first year of life, CTL drive the selection of de novo escape variants, which together with mother-to-child transmission of viruses preadapted to the HLA class I alleles expressed in the infant, are likely to contribute to a lack of immune control in pediatric infection.
We studied five rapidly progressing infants and their mothers from Durban, South Africa, from pregnancy to up to 1.5 years after birth (see Table S1 in the supplemental material). Three of the five infants died with HIV-1 disease within 3 to 23 months. A fourth infant commenced antiretroviral therapy at 1 year of age after the onset of AIDS. The fifth infant was withdrawn from the study by his guardians following the AIDS-related death of his mother.
To assess infant immunity-driven viral evolution, we examined HIV-1 viral genes encoding the most immunogenic viral proteins (1), Gag and Nef. gag and nef were sequenced from plasma RNAs collected from infants and mothers from pregnancy onwards. Phylogenetic analysis (22) confirmed the relatedness of clones from mother-child pairs, all of which clustered with clade C viruses (see Fig. S1 in the supplemental material).
At six epitopes from three infants, we identified de novo CTL escape (Table 1; see Table S2 in the supplemental material). Using the method of CODEML selection analysis as previously described (7), four of these antigenic sites were shown to be under positive selection in these infants (Table 1) (dn/ds > 1; P < 0.05). Maximum likelihood phylogenetic analysis indicated that in each case, the CTL escape variant had evolved subsequently in the infant (Fig. 1 and data not shown). No variation was observed at these sites in >50 clones from each mother sampled across different time points. This observation, together with phylogenetic evidence, suggests that the CTL escape viruses had arisen in the infants.
We next examined epitopes presented by alleles shared by mother and child to determine whether escape variants could be specifically selected in rapidly progressing infants. An analysis of nef from infant I4 demonstrated the selection of a Pro-to-Ser or -Gln change at position 2 of the HLA-B4201 epitope, TPGPGVRYPL, between 10 and 26 weeks postpartum (Table 1; Fig. 2a). These variant peptides generated specifically in the infant were not recognized (Fig. 2b) and did not bind to HLA-B4201 (Fig. 2c). These CTL escape mutants driven by selection pressure in the infant were absent from the B4201-positive mother, in spite of the presence of the same TL10-specific CTL response in the mother (Fig. 2d). The combination of a consistent high-frequency TL10-specific response and a persistent high maternal viral load of >100,000 HIV RNA copies/ml of plasma suggests that this particular response was ineffective (4, 24), whereas the same response in the infant "drove" the evolution of the escape variants early on in the infection. These data demonstrate that, at least for certain epitopes, selection for escape may operate during early pediatric HIV infection but may be absent from chronic adult infections.
It has previously been shown that children may be in a particularly disadvantaged position with respect to the epitopes available for an effective HIV-specific CTL response as a result of mother-to-child transmission of a virus that has adapted successfully to the maternal class I alleles (10, 15). Since infants typically share 50% of their HLA class I alleles with their mothers, it might be predicted that the remaining 50% of the infant's HLA alleles that are paternally inherited could be utilized more successfully to mount responses against maternally transmitted virus. However, in some cases, the maternal HIV infection may result from the transmission of virus from the child's father. To examine the question of whether viruses adapted to paternal HLA alleles may in this way be indirectly transmitted to the child via the mother, we sought "footprints" of paternal HLA alleles in viruses transmitted from mother to child. Previous studies of gag sequences from HLA-B57-positive subjects have identified "footprints" of HLA-B57 which persist following transmission to B57-negative subjects (16). In particular, these arise at Gag residues 219 (H219Q) and 248. For clade B infections, the characteristic B57 footprint is G248A, whereas for clade C infections, the B57 footprint at this site is A248T (P = 0.036) (16). The occurrence of such HLA-B57-associated polymorphisms in the HLA-B57-negative mother M5 (Fig. 3a) is thus indicative of the transmission of virus from an HLA-B57-positive subject to the mother (P = 0.008) (16). Since child I5 had HLA-B57, one may speculate that the HLA-B57-positive father in this instance directly transmitted a virus carrying these HLA-B57-associated mutations to the HLA-B57-negative mother, M5. These B57 "footprints" persisting in the mother were, in turn, transmitted to the HLA-B57-positive child. In this example, the transmitted variant A248T did not affect binding to HLA-B57, and thus a TW10 response (and further immune pressure on the virus) could be generated by the child. The transmission of an escape variant unable to bind to the HLA molecule would have precluded a response in the infant. One example of mother-to-child transmission of such a variant has been described for the B27-KK10 epitope, where Arg is required for binding to B27 (10, 11). We identified another example of this in a Barbadian mother-child pair (Fig. 3b), but with HLA-B27 being shared by the mother and child. In this instance, the presence of the B27 footprint R264X in the virus of the B27-negative father and a sequence analysis demonstrating the shared phylogeny of the paternal and maternal viruses (Fig. 3c) indicated that in this case, transmission of the virus occurred from mother to father. Analyses of these and other families show that HIV infection in one parent not infrequently is the result of transmission by the other parent (Fig. 3c), and thus the acquisition of a virus adapted to paternal and maternal HLA alleles may occur in the infant via mother-to-child transmission.
These data show that there are several unique influences that may compromise the effectiveness of the early pediatric HIV-specific immune response that involve CTL escape. These include the transmission of escape variants generated in the mother and also those originally generated in the father and the early development of escape mutations in epitopes at which selection for escape does not necessarily occur in adult infections. The occurrence of de novo escape during early pediatric infections implies, on the one hand, a suboptimal immune response akin to the development of drug-resistant mutations in the presence of suboptimal antiretroviral therapy. On the other hand, the presence of functional CTL generated against HIV in early infancy suggests the possibility that early immunomodulatory interventions may have promise to improve the efficacy of these CTL responses and bring about more successful HIV-specific control of pediatric infections in the future.
Supplemental material for this article may be found at http://jvi.asm.org/.
REFERENCES
Addo, M. M., X. G. Yu, A. Rathod, D. Cohen, R. L. Eldridge, D. Strick, M. N. Johnston, C. Corcoran, A. G. Wurcel, C. A. Fitzpatrick, M. E. Feeney, W. R. Rodriguez, N. Basgoz, R. Draenert, D. R. Stone, C. Brander, P. J. Goulder, E. S. Rosenberg, M. Altfeld, and B. D. Walker. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77:2081-2092.
Barouch, D. H., J. Kunstman, M. J. Kuroda, J. E. Schmitz, S. Santra, F. W. Peyerl, G. R. Krivulka, K. Beaudry, M. A. Lifton, D. A. Gorgone, D. C. Montefiori, M. G. Lewis, S. M. Wolinsky, and N. L. Letvin. 2002. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335-339.
Brander, C., P. J. Goulder, K. Luzuriaga, O. O. Yang, K. E. Hartman, N. G. Jones, B. D. Walker, and S. A. Kalams. 1999. Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection. J. Immunol. 162:4796-4800.
Buseyne, F., S. Blanche, D. Schmitt, C. Griscelli, and Y. Riviere. 1993. Detection of HIV-specific cell-mediated cytotoxicity in the peripheral blood from infected children. J. Immunol. 150:3569-3581.
Buseyne, F., M. Burgard, J. P. Teglas, E. Bui, C. Rouzioux, M. J. Mayaux, S. Blanche, and Y. Riviere. 1998. Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers. AIDS Res. Hum. Retrovir. 14:1435-1444.
Cheynier, R., P. Langlade-Demoyen, M. R. Marescot, S. Blanche, G. Blondin, S. Wain-Hobson, C. Griscelli, E. Vilmer, and F. Plata. 1992. Cytotoxic T lymphocyte responses in the peripheral blood of children born to human immunodeficiency virus-1-infected mothers. Eur. J. Immunol. 22:2211-2217.
Draenert, R., S. Le Gall, K. J. Pfafferott, A. J. Leslie, P. Chetty, C. Brander, E. C. Holmes, S. C. Chang, M. E. Feeney, M. M. Addo, L. Ruiz, D. Ramduth, P. Jeena, M. Altfeld, S. Thomas, Y. Tang, C. L. Verrill, C. Dixon, J. G. Prado, P. Kiepiela, J. Martinez-Picado, B. D. Walker, and P. J. Goulder. 2004. Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J. Exp. Med. 199:905-915.
Feeney, M. E., Y. Tang, K. A. Roosevelt, A. J. Leslie, K. McIntosh, N. Karthas, B. D. Walker, and P. J. Goulder. 2004. Immune escape precedes breakthrough human immunodeficiency virus type 1 viremia and broadening of the cytotoxic T-lymphocyte response in an HLA-B27-positive long-term-nonprogressing child. J. Virol. 78:8927-8930.
Gallagher, K., M. Gorre, N. Harawa, M. Dillon, D. Wafer, E. R. Stiehm, Y. Bryson, D. Song, R. Dickover, and S. Plaeger. 1997. Timing of lymphocyte activation in neonates infected with human immunodeficiency virus. Clin. Diagn. Lab. Immunol. 4:742-747.
Goulder, P. J., C. Brander, Y. Tang, C. Tremblay, R. A. Colbert, M. M. Addo, E. S. Rosenberg, T. Nguyen, R. Allen, A. Trocha, M. Altfeld, S. He, M. Bunce, R. Funkhouser, S. I. Pelton, S. K. Burchett, K. McIntosh, B. T. Korber, and B. D. Walker. 2001. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412:334-338.
Goulder, P. J., R. E. Phillips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, and S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212-217.
Jin, X., D. E. Bauer, S. E. Tuttleton, S. Lewin, A. Gettie, J. Blanchard, C. E. Irwin, J. T. Safrit, J. Mittler, L. Weinberger, L. G. Kostrikis, L. Zhang, A. S. Perelson, and D. D. Ho. 1999. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189:991-998.
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