Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jun 1;101(11):2559–2566. doi: 10.1172/JCI2405

Lack of strong immune selection pressure by the immunodominant, HLA-A*0201-restricted cytotoxic T lymphocyte response in chronic human immunodeficiency virus-1 infection.

C Brander 1, K E Hartman 1, A K Trocha 1, N G Jones 1, R P Johnson 1, B Korber 1, P Wentworth 1, S P Buchbinder 1, S Wolinsky 1, B D Walker 1, S A Kalams 1
PMCID: PMC508845  PMID: 9616227

Abstract

Despite detailed analysis of the HIV-1-specific cytotoxic T lymphocyte response by various groups, its relation to viral load and viral sequence variation remains controversial. We analyzed HLA-A*0201 restricted cytotoxic T lymphocyte responses in 17 HIV-1-infected individuals with viral loads ranging from < 400 to 221,000 HIV RNA molecules per milliliter of plasma. In 13 out of 17 infected subjects, CTL responses against the SLYNTVATL epitope (p17 Gag; aa 77-85) were detectable, whereas two other HLA-A*0201 restricted epitopes (ILKEPVHGV, IV9; and VIYQYMDDL, VL9) were only recognized by six and five individuals out of 17 individuals tested, respectively. Naturally occurring variants of the SL9 epitope were tested for binding to HLA-A*0201 and for recognition by specific T cell clones generated from five individuals. Although these variants were widely recognized, they differed by up to 10,000-fold in terms of variant peptide concentrations required for lysis of target cells. A comparison of viral sequences derived from 10 HLA-A*0201-positive individuals to sequences obtained from 11 HLA-A*0201-negative individuals demonstrated only weak evidence for immune selective pressure and thus question the in vivo efficacy of immunodominant CTL responses present during chronic HIV-1 infection.

Full Text

The Full Text of this article is available as a PDF (185.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aebischer T., Moskophidis D., Rohrer U. H., Zinkernagel R. M., Hengartner H. In vitro selection of lymphocytic choriomeningitis virus escape mutants by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11047–11051. doi: 10.1073/pnas.88.24.11047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bertoletti A., Costanzo A., Chisari F. V., Levrero M., Artini M., Sette A., Penna A., Giuberti T., Fiaccadori F., Ferrari C. Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J Exp Med. 1994 Sep 1;180(3):933–943. doi: 10.1084/jem.180.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bodmer J. G., Marsh S. G., Albert E. D., Bodmer W. F., Bontrop R. E., Charron D., Dupont B., Erlich H. A., Mach B., Mayr W. R. Nomenclature for factors of the HLA system, 1995. Tissue Antigens. 1995 Jul;46(1):1–18. doi: 10.1111/j.1399-0039.1995.tb02470.x. [DOI] [PubMed] [Google Scholar]
  4. Borrow P., Lewicki H., Hahn B. H., Shaw G. M., Oldstone M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994 Sep;68(9):6103–6110. doi: 10.1128/jvi.68.9.6103-6110.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Borrow P., Lewicki H., Wei X., Horwitz M. S., Peffer N., Meyers H., Nelson J. A., Gairin J. E., Hahn B. H., Oldstone M. B. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med. 1997 Feb;3(2):205–211. doi: 10.1038/nm0297-205. [DOI] [PubMed] [Google Scholar]
  6. Borysiewicz L. K., Graham S., Hickling J. K., Mason P. D., Sissons J. G. Human cytomegalovirus-specific cytotoxic T cells: their precursor frequency and stage specificity. Eur J Immunol. 1988 Feb;18(2):269–275. doi: 10.1002/eji.1830180214. [DOI] [PubMed] [Google Scholar]
  7. Brander C., Pichler W. J., Corradin G. Identification of HIV protein-derived cytotoxic T lymphocyte (CTL) epitopes for their possible use as synthetic vaccine. Clin Exp Immunol. 1995 Jul;101(1):107–113. doi: 10.1111/j.1365-2249.1995.tb02285.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Browning M., Krausa P. Genetic diversity of HLA-A2: evolutionary and functional significance. Immunol Today. 1996 Apr;17(4):165–170. doi: 10.1016/0167-5699(96)80614-1. [DOI] [PubMed] [Google Scholar]
  9. Buchbinder S. P., Katz M. H., Hessol N. A., Liu J., O'Malley P. M., Alter M. J. Hepatitis C virus infection in sexually active homosexual men. J Infect. 1994 Nov;29(3):263–269. doi: 10.1016/s0163-4453(94)91128-2. [DOI] [PubMed] [Google Scholar]
  10. Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Castaño A. R., López de Castro J. A. Structure of the HLA-A*0204 antigen, found in South American Indians. Spatial clustering of HLA-A2 subtype polymorphism. Immunogenetics. 1991;34(5):281–285. doi: 10.1007/BF00211991. [DOI] [PubMed] [Google Scholar]
  12. Chen Z. W., Shen L., Miller M. D., Ghim S. H., Hughes A. L., Letvin N. L. Cytotoxic T lymphocytes do not appear to select for mutations in an immunodominant epitope of simian immunodeficiency virus gag. J Immunol. 1992 Dec 15;149(12):4060–4066. [PubMed] [Google Scholar]
  13. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  14. Coffin J. M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995 Jan 27;267(5197):483–489. doi: 10.1126/science.7824947. [DOI] [PubMed] [Google Scholar]
  15. Couillin I., Culmann-Penciolelli B., Gomard E., Choppin J., Levy J. P., Guillet J. G., Saragosti S. Impaired cytotoxic T lymphocyte recognition due to genetic variations in the main immunogenic region of the human immunodeficiency virus 1 NEF protein. J Exp Med. 1994 Sep 1;180(3):1129–1134. doi: 10.1084/jem.180.3.1129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Driscoll J., Brown M. G., Finley D., Monaco J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature. 1993 Sep 16;365(6443):262–264. doi: 10.1038/365262a0. [DOI] [PubMed] [Google Scholar]
  17. Dupuis M., Kundu S. K., Merigan T. C. Characterization of HLA-A 0201-restricted cytotoxic T cell epitopes in conserved regions of the HIV type 1 gp160 protein. J Immunol. 1995 Aug 15;155(4):2232–2239. [PubMed] [Google Scholar]
  18. Goulder P. J., Phillips R. E., Colbert R. A., McAdam S., Ogg G., Nowak M. A., Giangrande P., Luzzi G., Morgan B., Edwards A. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med. 1997 Feb;3(2):212–217. doi: 10.1038/nm0297-212. [DOI] [PubMed] [Google Scholar]
  19. Goulder P. J., Sewell A. K., Lalloo D. G., Price D. A., Whelan J. A., Evans J., Taylor G. P., Luzzi G., Giangrande P., Phillips R. E. Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation. J Exp Med. 1997 Apr 21;185(8):1423–1433. doi: 10.1084/jem.185.8.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hadida F., Haas G., Zimmermann N., Hosmalin A., Spohn R., Samri A., Jung G., Debre P., Autran B. CTLs from lymphoid organs recognize an optimal HLA-A2-restricted and HLA-B52-restricted nonapeptide and several epitopes in the C-terminal region of HIV-1 Nef. J Immunol. 1995 Apr 15;154(8):4174–4186. [PubMed] [Google Scholar]
  21. Harrer E., Harrer T., Barbosa P., Feinberg M., Johnson R. P., Buchbinder S., Walker B. D. Recognition of the highly conserved YMDD region in the human immunodeficiency virus type 1 reverse transcriptase by HLA-A2-restricted cytotoxic T lymphocytes from an asymptomatic long-term nonprogressor. J Infect Dis. 1996 Feb;173(2):476–479. doi: 10.1093/infdis/173.2.476. [DOI] [PubMed] [Google Scholar]
  22. Heemels M. T., Ploegh H. L. Substrate specificity of allelic variants of the TAP peptide transporter. Immunity. 1994 Dec;1(9):775–784. doi: 10.1016/s1074-7613(94)80019-7. [DOI] [PubMed] [Google Scholar]
  23. Johnson R. P., Trocha A., Yang L., Mazzara G. P., Panicali D. L., Buchanan T. M., Walker B. D. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. Fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. J Immunol. 1991 Sep 1;147(5):1512–1521. [PubMed] [Google Scholar]
  24. Kalams S. A., Johnson R. P., Dynan M. J., Hartman K. E., Harrer T., Harrer E., Trocha A. K., Blattner W. A., Buchbinder S. P., Walker B. D. T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant. J Exp Med. 1996 Apr 1;183(4):1669–1679. doi: 10.1084/jem.183.4.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kalams S. A., Johnson R. P., Trocha A. K., Dynan M. J., Ngo H. S., D'Aquila R. T., Kurnick J. T., Walker B. D. Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J Exp Med. 1994 Apr 1;179(4):1261–1271. doi: 10.1084/jem.179.4.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Klein M. R., van Baalen C. A., Holwerda A. M., Kerkhof Garde S. R., Bende R. J., Keet I. P., Eeftinck-Schattenkerk J. K., Osterhaus A. D., Schuitemaker H., Miedema F. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med. 1995 Apr 1;181(4):1365–1372. doi: 10.1084/jem.181.4.1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klenerman P., Meier U. C., Phillips R. E., McMichael A. J. The effects of natural altered peptide ligands on the whole blood cytotoxic T lymphocyte response to human immunodeficiency virus. Eur J Immunol. 1995 Jul;25(7):1927–1931. doi: 10.1002/eji.1830250720. [DOI] [PubMed] [Google Scholar]
  28. Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994 Jul;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Koup R. A. Virus escape from CTL recognition. J Exp Med. 1994 Sep 1;180(3):779–782. doi: 10.1084/jem.180.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mellors J. W., Rinaldo C. R., Jr, Gupta P., White R. M., Todd J. A., Kingsley L. A. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167–1170. doi: 10.1126/science.272.5265.1167. [DOI] [PubMed] [Google Scholar]
  31. Meyerhans A., Dadaglio G., Vartanian J. P., Langlade-Demoyen P., Frank R., Asjö B., Plata F., Wain-Hobson S. In vivo persistence of a HIV-1-encoded HLA-B27-restricted cytotoxic T lymphocyte epitope despite specific in vitro reactivity. Eur J Immunol. 1991 Oct;21(10):2637–2640. doi: 10.1002/eji.1830211051. [DOI] [PubMed] [Google Scholar]
  32. Neisig A., Wubbolts R., Zang X., Melief C., Neefjes J. Allele-specific differences in the interaction of MHC class I molecules with transporters associated with antigen processing. J Immunol. 1996 May 1;156(9):3196–3206. [PubMed] [Google Scholar]
  33. Niedermann G., Butz S., Ihlenfeldt H. G., Grimm R., Lucchiari M., Hoschützky H., Jung G., Maier B., Eichmann K. Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. Immunity. 1995 Mar;2(3):289–299. doi: 10.1016/1074-7613(95)90053-5. [DOI] [PubMed] [Google Scholar]
  34. Nietfield W., Bauer M., Fevrier M., Maier R., Holzwarth B., Frank R., Maier B., Riviere Y., Meyerhans A. Sequence constraints and recognition by CTL of an HLA-B27-restricted HIV-1 gag epitope. J Immunol. 1995 Mar 1;154(5):2189–2197. [PubMed] [Google Scholar]
  35. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. doi: 10.1126/science.271.5255.1582. [DOI] [PubMed] [Google Scholar]
  36. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  37. Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
  38. Plata F., Autran B., Martins L. P., Wain-Hobson S., Raphaël M., Mayaud C., Denis M., Guillon J. M., Debré P. AIDS virus-specific cytotoxic T lymphocytes in lung disorders. Nature. 1987 Jul 23;328(6128):348–351. doi: 10.1038/328348a0. [DOI] [PubMed] [Google Scholar]
  39. Price D. A., Goulder P. J., Klenerman P., Sewell A. K., Easterbrook P. J., Troop M., Bangham C. R., Phillips R. E. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1890–1895. doi: 10.1073/pnas.94.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rammensee H. G., Falk K., Rötzschke O. MHC molecules as peptide receptors. Curr Opin Immunol. 1993 Feb;5(1):35–44. doi: 10.1016/0952-7915(93)90078-7. [DOI] [PubMed] [Google Scholar]
  41. Rosenberg E. S., Billingsley J. M., Caliendo A. M., Boswell S. L., Sax P. E., Kalams S. A., Walker B. D. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997 Nov 21;278(5342):1447–1450. doi: 10.1126/science.278.5342.1447. [DOI] [PubMed] [Google Scholar]
  42. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  43. Safrit J. T., Andrews C. A., Zhu T., Ho D. D., Koup R. A. Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: recognition of autologous virus sequences within a conserved immunodominant epitope. J Exp Med. 1994 Feb 1;179(2):463–472. doi: 10.1084/jem.179.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sette A., Sidney J., del Guercio M. F., Southwood S., Ruppert J., Dahlberg C., Grey H. M., Kubo R. T. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol Immunol. 1994 Aug;31(11):813–822. doi: 10.1016/0161-5890(94)90019-1. [DOI] [PubMed] [Google Scholar]
  45. Sette A., Vitiello A., Reherman B., Fowler P., Nayersina R., Kast W. M., Melief C. J., Oseroff C., Yuan L., Ruppert J. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol. 1994 Dec 15;153(12):5586–5592. [PubMed] [Google Scholar]
  46. Tsomides T. J., Aldovini A., Johnson R. P., Walker B. D., Young R. A., Eisen H. N. Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J Exp Med. 1994 Oct 1;180(4):1283–1293. doi: 10.1084/jem.180.4.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tsomides T. J., Walker B. D., Eisen H. N. An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11276–11280. doi: 10.1073/pnas.88.24.11276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wain-Hobson S. The fastest genome evolution ever described: HIV variation in situ. Curr Opin Genet Dev. 1993 Dec;3(6):878–883. doi: 10.1016/0959-437x(93)90008-d. [DOI] [PubMed] [Google Scholar]
  49. Walker B. D., Chakrabarti S., Moss B., Paradis T. J., Flynn T., Durno A. G., Blumberg R. S., Kaplan J. C., Hirsch M. S., Schooley R. T. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature. 1987 Jul 23;328(6128):345–348. doi: 10.1038/328345a0. [DOI] [PubMed] [Google Scholar]
  50. Walker B. D., Flexner C., Birch-Limberger K., Fisher L., Paradis T. J., Aldovini A., Young R., Moss B., Schooley R. T. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9514–9518. doi: 10.1073/pnas.86.23.9514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Walker B. D., Flexner C., Paradis T. J., Fuller T. C., Hirsch M. S., Schooley R. T., Moss B. HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. Science. 1988 Apr 1;240(4848):64–66. doi: 10.1126/science.2451288. [DOI] [PubMed] [Google Scholar]
  52. Weiner A., Erickson A. L., Kansopon J., Crawford K., Muchmore E., Hughes A. L., Houghton M., Walker C. M. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2755–2759. doi: 10.1073/pnas.92.7.2755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wolinsky S. M., Korber B. T., Neumann A. U., Daniels M., Kunstman K. J., Whetsell A. J., Furtado M. R., Cao Y., Ho D. D., Safrit J. T. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science. 1996 Apr 26;272(5261):537–542. doi: 10.1126/science.272.5261.537. [DOI] [PubMed] [Google Scholar]
  54. Wu T. T., Kabat E. A. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med. 1970 Aug 1;132(2):211–250. doi: 10.1084/jem.132.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yang O. O., Kalams S. A., Rosenzweig M., Trocha A., Jones N., Koziel M., Walker B. D., Johnson R. P. Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J Virol. 1996 Sep;70(9):5799–5806. doi: 10.1128/jvi.70.9.5799-5806.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yang O. O., Kalams S. A., Trocha A., Cao H., Luster A., Johnson R. P., Walker B. D. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol. 1997 Apr;71(4):3120–3128. doi: 10.1128/jvi.71.4.3120-3128.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. de Campos-Lima P. O., Gavioli R., Zhang Q. J., Wallace L. E., Dolcetti R., Rowe M., Rickinson A. B., Masucci M. G. HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population. Science. 1993 Apr 2;260(5104):98–100. doi: 10.1126/science.7682013. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES