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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Nov 1;102(9):1758–1765. doi: 10.1172/JCI4314

Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi.

S L Rowland-Jones 1, T Dong 1, K R Fowke 1, J Kimani 1, P Krausa 1, H Newell 1, T Blanchard 1, K Ariyoshi 1, J Oyugi 1, E Ngugi 1, J Bwayo 1, K S MacDonald 1, A J McMichael 1, F A Plummer 1
PMCID: PMC509124  PMID: 9802890

Abstract

Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

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Selected References

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  1. Ada G. L., McElrath M. J. HIV type 1 vaccine-induced cytotoxic T cell responses: potential role in vaccine efficacy. AIDS Res Hum Retroviruses. 1997 Feb 10;13(3):205–210. doi: 10.1089/aid.1997.13.205. [DOI] [PubMed] [Google Scholar]
  2. Anzala A. O., Ball T. B., Rostron T., O'Brien S. J., Plummer F. A., Rowland-Jones S. L. CCR2-64I allele and genotype association with delayed AIDS progression in African women. University of Nairobi Collaboration for HIV Research. Lancet. 1998 May 30;351(9116):1632–1633. doi: 10.1016/s0140-6736(05)77688-1. [DOI] [PubMed] [Google Scholar]
  3. Anzala O. A., Nagelkerke N. J., Bwayo J. J., Holton D., Moses S., Ngugi E. N., Ndinya-Achola J. O., Plummer F. A. Rapid progression to disease in African sex workers with human immunodeficiency virus type 1 infection. J Infect Dis. 1995 Mar;171(3):686–689. doi: 10.1093/infdis/171.3.686. [DOI] [PubMed] [Google Scholar]
  4. Barouch D., Friede T., Stevanović S., Tussey L., Smith K., Rowland-Jones S., Braud V., McMichael A., Rammensee H. G. HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J Exp Med. 1995 Dec 1;182(6):1847–1856. doi: 10.1084/jem.182.6.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bertoni R., Sidney J., Fowler P., Chesnut R. W., Chisari F. V., Sette A. Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest. 1997 Aug 1;100(3):503–513. doi: 10.1172/JCI119559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Betts M. R., Krowka J., Santamaria C., Balsamo K., Gao F., Mulundu G., Luo C., N'Gandu N., Sheppard H., Hahn B. H. Cross-clade human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte responses in HIV-infected Zambians. J Virol. 1997 Nov;71(11):8908–8911. doi: 10.1128/jvi.71.11.8908-8911.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bunce M., O'Neill C. M., Barnardo M. C., Krausa P., Browning M. J., Morris P. J., Welsh K. I. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens. 1995 Nov;46(5):355–367. doi: 10.1111/j.1399-0039.1995.tb03127.x. [DOI] [PubMed] [Google Scholar]
  8. Cao H., Kanki P., Sankalé J. L., Dieng-Sarr A., Mazzara G. P., Kalams S. A., Korber B., Mboup S., Walker B. D. Cytotoxic T-lymphocyte cross-reactivity among different human immunodeficiency virus type 1 clades: implications for vaccine development. J Virol. 1997 Nov;71(11):8615–8623. doi: 10.1128/jvi.71.11.8615-8623.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Dean M., Carrington M., Winkler C., Huttley G. A., Smith M. W., Allikmets R., Goedert J. J., Buchbinder S. P., Vittinghoff E., Gomperts E. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science. 1996 Sep 27;273(5283):1856–1862. doi: 10.1126/science.273.5283.1856. [DOI] [PubMed] [Google Scholar]
  11. Ferrari G., Humphrey W., McElrath M. J., Excler J. L., Duliege A. M., Clements M. L., Corey L. C., Bolognesi D. P., Weinhold K. J. Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1396–1401. doi: 10.1073/pnas.94.4.1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fowke K. R., Dong T., Rowland-Jones S. L., Oyugi J., Rutherford W. J., Kimani J., Krausa P., Bwayo J., Simonsen J. N., Shearer G. M. HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced beta-chemokine production. AIDS Res Hum Retroviruses. 1998 Nov 20;14(17):1521–1530. doi: 10.1089/aid.1998.14.1521. [DOI] [PubMed] [Google Scholar]
  13. Fowke K. R., Nagelkerke N. J., Kimani J., Simonsen J. N., Anzala A. O., Bwayo J. J., MacDonald K. S., Ngugi E. N., Plummer F. A. Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet. 1996 Nov 16;348(9038):1347–1351. doi: 10.1016/S0140-6736(95)12269-2. [DOI] [PubMed] [Google Scholar]
  14. Huang Y., Paxton W. A., Wolinsky S. M., Neumann A. U., Zhang L., He T., Kang S., Ceradini D., Jin Z., Yazdanbakhsh K. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996 Nov;2(11):1240–1243. doi: 10.1038/nm1196-1240. [DOI] [PubMed] [Google Scholar]
  15. Khanna R., Burrows S. R., Nicholls J., Poulsen L. M. Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol. 1998 Feb;28(2):451–458. doi: 10.1002/(SICI)1521-4141(199802)28:02<451::AID-IMMU451>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  16. Lalvani A., Brookes R., Hambleton S., Britton W. J., Hill A. V., McMichael A. J. Rapid effector function in CD8+ memory T cells. J Exp Med. 1997 Sep 15;186(6):859–865. doi: 10.1084/jem.186.6.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lalvani A., Brookes R., Wilkinson R. J., Malin A. S., Pathan A. A., Andersen P., Dockrell H., Pasvol G., Hill A. V. Human cytolytic and interferon gamma-secreting CD8+ T lymphocytes specific for Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):270–275. doi: 10.1073/pnas.95.1.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lalvani A., Dong T., Ogg G., Patham A. A., Newell H., Hill A. V., McMichael A. J., Rowland-Jones S. Optimization of a peptide-based protocol employing IL-7 for in vitro restimulation of human cytotoxic T lymphocyte precursors. J Immunol Methods. 1997 Dec 15;210(1):65–77. doi: 10.1016/s0022-1759(97)00177-4. [DOI] [PubMed] [Google Scholar]
  19. Mammano F., Ohagen A., Höglund S., Göttlinger H. G. Role of the major homology region of human immunodeficiency virus type 1 in virion morphogenesis. J Virol. 1994 Aug;68(8):4927–4936. doi: 10.1128/jvi.68.8.4927-4936.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Martinson J. J., Chapman N. H., Rees D. C., Liu Y. T., Clegg J. B. Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet. 1997 May;16(1):100–103. doi: 10.1038/ng0597-100. [DOI] [PubMed] [Google Scholar]
  21. Mazzoli S., Trabattoni D., Lo Caputo S., Piconi S., Blé C., Meacci F., Ruzzante S., Salvi A., Semplici F., Longhi R. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat Med. 1997 Nov;3(11):1250–1257. doi: 10.1038/nm1197-1250. [DOI] [PubMed] [Google Scholar]
  22. McAdam S., Kaleebu P., Krausa P., Goulder P., French N., Collin B., Blanchard T., Whitworth J., McMichael A., Gotch F. Cross-clade recognition of p55 by cytotoxic T lymphocytes in HIV-1 infection. AIDS. 1998 Apr 16;12(6):571–579. doi: 10.1097/00002030-199806000-00005. [DOI] [PubMed] [Google Scholar]
  23. Michael N. L., Chang G., Louie L. G., Mascola J. R., Dondero D., Birx D. L., Sheppard H. W. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. Nat Med. 1997 Mar;3(3):338–340. doi: 10.1038/nm0397-338. [DOI] [PubMed] [Google Scholar]
  24. Moses S., Plummer F. A., Ngugi E. N., Nagelkerke N. J., Anzala A. O., Ndinya-Achola J. O. Controlling HIV in Africa: effectiveness and cost of an intervention in a high-frequency STD transmitter core group. AIDS. 1991 Apr;5(4):407–411. [PubMed] [Google Scholar]
  25. Nixon D. F., Townsend A. R., Elvin J. G., Rizza C. R., Gallwey J., McMichael A. J. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature. 1988 Dec 1;336(6198):484–487. doi: 10.1038/336484a0. [DOI] [PubMed] [Google Scholar]
  26. Ogg G. S., Dong T., Hansasuta P., Dorrell L., Clarke J., Coker R., Luzzi G., Conlon C., McMichael A. P., Rowland-Jones S. Four novel cytotoxic T-lymphocyte epitopes in the highly conserved major homology region of HIV-1 Gag, restricted through B*4402, B*1801, A*2601, B*70 (B*1509) AIDS. 1998 Aug 20;12(12):1561–1563. doi: 10.1097/00002030-199812000-00026. [DOI] [PubMed] [Google Scholar]
  27. Paxton W. A., Martin S. R., Tse D., O'Brien T. R., Skurnick J., VanDevanter N. L., Padian N., Braun J. F., Kotler D. P., Wolinsky S. M. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med. 1996 Apr;2(4):412–417. doi: 10.1038/nm0496-412. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Pinto L. A., Sullivan J., Berzofsky J. A., Clerici M., Kessler H. A., Landay A. L., Shearer G. M. ENV-specific cytotoxic T lymphocyte responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. J Clin Invest. 1995 Aug;96(2):867–876. doi: 10.1172/JCI118133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Poss M., Gosink J., Thomas E., Kreiss J. K., Ndinya-Achola J., Mandaliya K., Bwayo J., Overbaugh J. Phylogenetic evaluation of Kenyan HIV type 1 isolates. AIDS Res Hum Retroviruses. 1997 Apr 10;13(6):493–499. doi: 10.1089/aid.1997.13.493. [DOI] [PubMed] [Google Scholar]
  31. Putkonen P., Mäkitalo B., Böttiger D., Biberfeld G., Thorstensson R. Protection of human immunodeficiency virus type 2-exposed seronegative macaques from mucosal simian immunodeficiency virus transmission. J Virol. 1997 Jul;71(7):4981–4984. doi: 10.1128/jvi.71.7.4981-4984.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Quillent C., Oberlin E., Braun J., Rousset D., Gonzalez-Canali G., Métais P., Montagnier L., Virelizier J. L., Arenzana-Seisdedos F., Beretta A. HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene. Lancet. 1998 Jan 3;351(9095):14–18. doi: 10.1016/S0140-6736(97)09185-X. [DOI] [PubMed] [Google Scholar]
  33. Rowland-Jones S. L., McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol. 1995 Aug;7(4):448–455. doi: 10.1016/0952-7915(95)80087-5. [DOI] [PubMed] [Google Scholar]
  34. Rowland-Jones S. L., Nixon D. F., Aldhous M. C., Gotch F., Ariyoshi K., Hallam N., Kroll J. S., Froebel K., McMichael A. HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet. 1993 Apr 3;341(8849):860–861. doi: 10.1016/0140-6736(93)93063-7. [DOI] [PubMed] [Google Scholar]
  35. Rowland-Jones S., Sutton J., Ariyoshi K., Dong T., Gotch F., McAdam S., Whitby D., Sabally S., Gallimore A., Corrah T. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med. 1995 Jan;1(1):59–64. doi: 10.1038/nm0195-59. [DOI] [PubMed] [Google Scholar]
  36. Samson M., Libert F., Doranz B. J., Rucker J., Liesnard C., Farber C. M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996 Aug 22;382(6593):722–725. doi: 10.1038/382722a0. [DOI] [PubMed] [Google Scholar]
  37. Shearer G. M., Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today. 1996 Jan;17(1):21–24. doi: 10.1016/0167-5699(96)80564-0. [DOI] [PubMed] [Google Scholar]
  38. Threlkeld S. C., Wentworth P. A., Kalams S. A., Wilkes B. M., Ruhl D. J., Keogh E., Sidney J., Southwood S., Walker B. D., Sette A. Degenerate and promiscuous recognition by CTL of peptides presented by the MHC class I A3-like superfamily: implications for vaccine development. J Immunol. 1997 Aug 15;159(4):1648–1657. [PubMed] [Google Scholar]
  39. Zhang C., Cui Y., Houston S., Chang L. J. Protective immunity to HIV-1 in SCID/beige mice reconstituted with peripheral blood lymphocytes of exposed but uninfected individuals. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14720–14725. doi: 10.1073/pnas.93.25.14720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. del Guercio M. F., Sidney J., Hermanson G., Perez C., Grey H. M., Kubo R. T., Sette A. Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. J Immunol. 1995 Jan 15;154(2):685–693. [PubMed] [Google Scholar]

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