Higher macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels from CD8+ T cells are associated with asymptomatic HIV-1 infection.
Journal: 2001/January - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
To test the hypothesis that beta-chemokine levels may be relevant to the control of HIV in vivo, we compared RANTES, MIP-1alpha, and MIP-1beta production from purified CD8(+) T cells from 81 HIV-infected subjects and from 28 uninfected donors. Asymptomatic HIV(+) subjects produced significantly higher levels of MIP-1alpha and MIP-1beta, but not RANTES, than uninfected donors or patients that progressed to AIDS. In contrast, beta chemokines in plasma were either nondetectable or showed no correlation with clinical status. The high beta-chemokine-mediated anti-HIV activity was against the macrophage tropic isolate HIV-1(BAL), with no demonstrable effect on the replication of the T-cell tropic HIV-1(IIIB). These findings suggest that constitutive beta-chemokine production may play an important role in the outcome of HIV-1 infection.
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Proc Natl Acad Sci U S A 97(25): 13812-13817

Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8<sup>+</sup> T cells are associated with asymptomatic HIV-1 infection

Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland, 725 West Lombard Street, Baltimore, MD 21201-1192; and HIV and AIDS Malignancy Branch, National Cancer Institute, 10 Center Drive, Room 12N226, National Institutes of Health, Bethesda, MD 20892
To whom reprint requests should be addressed. E-mail: ude.dmu.ibmu@ihccoc.
Contributed by Robert C. Gallo
Contributed by Robert C. Gallo
Accepted 2000 Oct 4.

Abstract

To test the hypothesis that β-chemokine levels may be relevant to the control of HIV in vivo, we compared RANTES, MIP-1α, and MIP-1β production from purified CD8 T cells from 81 HIV-infected subjects and from 28 uninfected donors. Asymptomatic HIV subjects produced significantly higher levels of MIP-1α and MIP-1β, but not RANTES, than uninfected donors or patients that progressed to AIDS. In contrast, β chemokines in plasma were either nondetectable or showed no correlation with clinical status. The high β-chemokine-mediated anti-HIV activity was against the macrophage tropic isolate HIV-1BAL, with no demonstrable effect on the replication of the T-cell tropic HIV-1IIIB. These findings suggest that constitutive β-chemokine production may play an important role in the outcome of HIV-1 infection.

Abstract

Immune control of HIV-1 infection by CD8 T cells appears to be mediated in part by HLA class I restricted cytolytic processes (1). Virus-specific cytotoxic T lymphocytes have been detected in exposed but uninfected individuals (2, 3). Anti-HIV-1 cytotoxic T-lymphocyte activity correlates with the down-regulation of viremia early in infection (4, 5) and with slower disease progression (6, 7). Further, a strong inverse correlation was recently described between the frequency of HIV-1-specific CD8 T cells that bind peptide–MHC tetramers and viral load for individuals undergoing highly active antiretroviral therapy (8). The contribution of CD8 T lymphocytes in controlling viremia is further supported by animal studies (9, 10). CD8 T lymphocytes can also suppress HIV replication in vitro by a nonlytic mechanism (11), and this antiviral activity is mediated by a soluble factor(s) (12, 13).

The noncytolytic antiviral response of CD8 T cells is present soon after infection and is associated with a decrease in plasma viremia (14). This antiviral activity has been correlated directly with the clinical stage of HIV-1 infection (1517).

In a previous study, we characterized three β chemokines released by activated CD8 T cells, RANTES, macrophage inflammatory protein (MIP)-1α, and MIP-1β, as the major factors responsible for soluble suppressor activity against macrophage tropic HIV-1 isolates (18). It is now established that RANTES, MIP-1α, and MIP-1β bind to a receptor, CC chemokine receptor 5 (CCR5), that is also required by macrophage tropic HIV-1 strains as a coreceptor for entry into host cells (19, 20). More recent studies showed this receptor-ligand binding renders CCR5 unavailable to the virus either by competitively blocking virus interactions or by causing down-regulation from host-cell surfaces (21, 22). T-cell tropic HIV-1 isolates are instead characterized by the usage of another chemokine receptor, CXC chemokine receptor 4 (CXCR4) (23), and the α chemokine stromal-derived factor 1 (SDF-1), a ligand for CXCR4, was shown to suppress replication of T-cell tropic HIV-1 isolates (24, 25). The profound impact of reduced coreceptor accessibility on HIV infection in vivo is strongly supported by evidence that individuals homozygous for a mutant CCR5 allele encoding a fusion-defective molecule (Δ32) are strongly resistant to infection (26, 27). Moreover, the heterozygous condition provides a limited resistance to disease progression (28, 29).

Collectively, these findings suggest that antiviral immunity might also be afforded via the release of HIV-suppressive chemokines from activated CD8 T cells because these chemokines down-regulate CCR5. However, the issue of the effects of increased production of inhibitory β chemokines in HIV infection and pathogenesis is still unsettled. In HIV-1-exposed but -uninfected individuals, an association between overproduction of β chemokines by CD4 T cells and resistance to in vitro infection with HIV-1 macrophage tropic isolates has been described (30). Moreover, in a cohort of uninfected hemophiliacs, despite repeated exposure to contaminated blood products, protection has been associated with the ability of peripheral blood mononuclear cells (PBMCs) to produce higher levels of RANTES, MIP-1α, and MIP-1β compared with hemophiliacs who were never treated with contaminated blood products (31). A specific immune response involving a high production of β chemokines by CD4 T cells seems to play a role of protection in exposed uninfected individuals (32) and may contribute to the control of viral replication in long-term nonprogressors (33). Higher β-chemokine secretion by PBMCs has been described in nonprogressors compared with rapid progressors (34), and higher production of MIP-1β by PBMCs has been associated with an asymptomatic status and decreased risk of disease progression (35). Antigen-induced chemokine production is also significantly decreased in HIV subjects with AIDS compared with asymptomatic HIV subjects (36). In accordance with these findings, sustained suppression of plasma HIV RNA is associated with an increase in the production of mitogen-induced MIP-1α and MIP-1β (37). Moreover, recent results indicate that human alloimmunization elicits very significant increases in the three β chemokines RANTES, MIP-1α, and MIP-1β, and resistance of CD4 T cells to HIV infection with macrophage-tropic HIV-1 strains (38). However, when the production of β chemokines by unfractionated PBMCs, purified CD4, or CD8 T cells was examined in small numbers of HIV-1 positive subjects, the analysis failed to demonstrate any association between chemokine levels and disease stage (39, 40). Furthermore, plasma levels of β chemokines did not reveal any substantial differences between progressors and nonprogressors (4146). Thus, conclusive evidence for the clinical relevance of CD8 T-cell β-chemokine-mediated antiviral activity in the natural history of HIV-1 infection in vivo is still lacking.

To examine this issue, we performed cross-sectional analyses of RANTES, MIP-1α, and MIP-1β production by purified CD8 T cells from 81 HIV-1-infected subjects at various stages of disease and from 28 uninfected donors. We analyzed the correlation between β-chemokine production and antiviral activity in vitro by using the macrophage tropic HIV-1BAL. The effect of anti-β-chemokine-neutralizing antibodies (NAb) on the CD8 T-cell-mediated antiviral activity was also studied. Moreover, we determined whether circulating levels of β chemokines reflect the ability of immunocompetent T cells to produce these molecules by comparing CD8 T-cell-mediated production with plasma levels measured in the same blood sample. Additionally, because of recent reports suggesting the potential for these chemokines to enhance HIV replication of T-cell tropic HIV-1 strains (47, 48), we determined whether RANTES, MIP-1α, and MIP-1β produced by activated CD8 T cells could enhance virus spread of the T-cell tropic HIV-1IIIB by using an acute infectivity assay. Finally, in this study, we addressed the question of whether the α-chemokine SDF-1 plays a role in CD8 T-cell-mediated antiviral activity against the T-cell tropic HIV-1IIIB.

Maximum number, 81 HIV-1 cases; lower numbers reflect missing data; Sig., significant; N, number of samples.

Acknowledgments

We thank Anne Sill for her skillful help with the statistical analysis, Kristin Wilson and Lewis Davis for their excellent technical help, and Yvette Gordon and Anna Mazzuca for their editorial assistance. This work was funded by National Institutes of Health Grant R21AI44735.

Acknowledgments

Abbreviations

MIPmacrophage inflammatory protein
NAbneutralizing antibodies
PBMCsperipheral blood mononuclear cells
PHAphytohemagglutinin
Rh IL-2recombinant human IL-2
CCR5CC chemokine receptor 5
SDF-1stromal-derived factor 1
Abbreviations

Footnotes

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.240469997.

Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.240469997

Footnotes

References

  • 1. Tsubota H, Lord C I, Watkins D I, Morimoto C, Letvin N L. J Exp Med. 1989;169:1421–1434.
  • 2. Langlade-Demoyen P, Ngo-Giang H, Ferchal F, Oksenhendler E. J Clin Invest. 1993;93:1293–1297.
  • 3. Rowland-Jones S, Sutton J, Ariyoshi K, Dong T, Gotch F, McAdam S, Whitby D, Sabally S, Gallimore A, Corrah T, et al Nat Med. 1995;1:59–64.[PubMed][Google Scholar]
  • 4. Koup R A, Safrit J T, Cao Y, Andrews C A, McLeod G, Borkowsky W, Farthing C, Ho D D. J Virol. 1994;68:4650–4655.
  • 5. Borrow P, Lewicki H, Hahn B H, Shaw G M, Oldstone M B A. J Virol. 1994;68:6103–6110.
  • 6. Rinaldo C, Huang X L, Fan Z F, Ding M, Beltz L, Logar A, Panicali D, Mazzara G, Liebmann J, Cottrill M, et al J Virol. 1995;69:5838–5842.[Google Scholar]
  • 7. Klein M R, van Baalen C A, Holwerda A M, Kerkhof Garde S R, Bende R J, Keet I P M, Eeftinck-Schattenkerk J-K M, Osterhaus A D M E, Schuitemaker H, Miedema F. J Exp Med. 1995;181:1365–1372.
  • 8. Ogg G S, Jin X, Bonhoeffer S, Dunbar P R, Nowak M A, Monard S, Segal J P, Cao Y, Rowland-Jones S L, Cerundolo V, et al Science. 1998;279:2103–2106.[PubMed][Google Scholar]
  • 9. Schmitz J E, Kuroda M J, Santra S, Sasseville V G, Simon M A, Lifton M A, Racz P, Tenner-Racz K, Dalesandro M, Scallon B J, et al Science. 1999;283:857–860.[PubMed][Google Scholar]
  • 10. Kuroda M J, Schmitz J E, Charini W A, Nickerson C E, Lifton M A, Lord C I, Forman M A, Letvin N L. J Immunol. 1999;162:5127–5133.[PubMed]
  • 11. Walker C M, Moody D J, Stites D P, Levy J A. Science. 1986;234:1563–1566.[PubMed]
  • 12. Walker C M, Levy J A. Immunology. 1989;66:628–630.
  • 13. Brinchmann J E, Gaudernack G, Vartdal F. J Immunol. 1990;144:2961–2966.[PubMed]
  • 14. Mackewicz C E, Yang L C, Lifson J D, Levy J A. Lancet. 1994;344:1671–1673.[PubMed]
  • 15. Gomez A M, Smaill F M, Rosenthal K L. Clin Exp Immunol. 1994;97:68–75.
  • 16. Mackewicz C E, Ortega H W, Levy J A. J Clin Invest. 1991;87:1462–1466.
  • 17. Blackbourn D J, Mackewicz C E, Barker E, Hunt T K, Herndier B, Haase A T, Levy J A. Proc Natl Acad Sci USA. 1996;93:13125–13130.
  • 18. Cocchi F, DeVico A L, Garzino-Demo A, Arya S K, Gallo R C, Lusso P. Science. 1995;270:1811–1815.[PubMed]
  • 19. Dragic T, Litwin V, Allaway G P, Martin S R, Huang Y, Nagashima K A, Cayanan C, Maddon P J, Koup R A, Moore J P, Paxton W A. Nature (London) 1996;381:667–673.[PubMed]
  • 20. Doranz B J, Rucker J, Yi Y, Smyth R J, Samson M, Peiper S C, Parmentier M, Collman R G, Doms R W. Cell. 1996;85:1149–1158.[PubMed]
  • 21. Amara A, Gall S L, Schwartz O, Salamero J, Montes M, Loetscher P, Baggiolini M, Virelizier J L, Arenzana-Seisdedos F. J Exp Med. 1997;186:139–146.
  • 22. Alkhatib G, Locati M, Kennedy P E, Murphy P M, Berger E A. Virology. 1997;234:340–348.[PubMed]
  • 23. Feng Y, Broder C C, Kennedy P E, Berger E A. Science. 1996;272:872–877.[PubMed]
  • 24. Bleul C C, Farzan M, Choe H, Prolin C, Clark-Lewis I, Sodroski J, Springer T A. Nature (London) 1996;382:829–833.[PubMed]
  • 25. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier J L, Arenzana-Seisdedos F, Schwartz O, Heard J M, Clark-Lewis I, Legler D F, et al Nature (London) 1996;382:833–835.[PubMed][Google Scholar]
  • 26. Dean M, Carrington M, Winkler C, Huttley G A, Smith M W, Allikmets R, Goedert J J, Buchbinder S P, Vittinghoff E, Gomperts E, et al Science. 1996;273:1856–1862. , and erratum (1996) 274, 1069. [[PubMed][Google Scholar]
  • 27. Michael N L, Chang G, Louie L G, Mascola J R, Dondero D, Birx D L, Sheppard H W. Nat Med. 1997;3:338–340.[PubMed]
  • 28. Eugen-Olsen J, Iversen A K N, Garred P, Koppelhus U, Pedersen C, Benfield T L, Sorensen A M, Katzenstein T, Dickmeiss E, Gerstoft J, et al AIDS. 1997;11:305–310.[PubMed][Google Scholar]
  • 29. De Roda Husman A M, Koot M, Cornelissen M, Keet I P, Brouwer M, Broersen S M, Bakker M, Ross M T, Prins M, deWolf F, et al Ann Intern Med. 1997;127:882–890.[PubMed][Google Scholar]
  • 30. 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, Koup R A. Nat Med. 1996;2:412–417.[PubMed]
  • 31. Zagury D, Lachgar A, Chams V, Fall L S, Bernard J, Zagury J F, Bizzini B, Gringeri A, Santagostino E, Rappaport J, et al Proc Natl Acad Sci USA. 1998;95:3857–3861.[Google Scholar]
  • 32. Furci L, Scarlatti G, Burastero S, Tambussi G, Colognesi C, Quillent C, Longhi R, Loverro P, Borgonovo B, Gaffi D, et al J Exp Med. 1997;186:455–460.[Google Scholar]
  • 33. Rosenberg E S, Billingsley J M, Caliendo A M, Boswell S L, Sax P E, Kalams S A, Walker B D. Science. 1997;278:1447–1450.[PubMed]
  • 34. Zagury D, Lachgar A, Chams V, Fall L S, Bernard J, Zagury J F, Bizzini B, Gringeri A, Santagostino E, Rappaport J, et al Proc Natl Acad Sci USA. 1998;95:3851–3856.[Google Scholar]
  • 35. Ullum H, Cozzi A, Victor J, Aladdin A, Phillips A N, Gerstoft J, Skinhej P, Pederson B K. J Infect Dis. 1998;177:331–336.[PubMed]
  • 36. Garzino-Demo A, Moss R B, Margolick J B, Cleghorn F, Sill A, Blattner W A, Cocchi F, Carlo D J, DeVico A L, Gallo R C. Proc Natl Acad Sci USA. 1999;96:11986–11991.
  • 37. Kumar D, Parato K, Kumar A, Sun E, Cameron D W, Angel J B. AIDS Res Hum Retroviruses. 1999;15:1073–1077.[PubMed]
  • 38. Wang Y, Tao L, Mitchell E, Bravery C, Berlingieri P, Armstrong P, Vaughan R, Underwood J, Lehner T. Nat Med. 1999;5:1004–1009.[PubMed]
  • 39. Blazevic V, Heino M, Ranki A, Jussila T, Krohn K J. AIDS. 1996;10:1435–1436.[PubMed]
  • 40. Clerici M, Balotta C, Trabattoni D, Papagno L, Ruzzante S, Rusconi S, Fusi M L, Colombo M C, Galli M. AIDS. 1996;10:1432–1433.[PubMed]
  • 41. Zanussi S, D'Andrea M, Simonelli C, Tirelli U, De Paoli P. AIDS. 1996;10:1431–1432.[PubMed]
  • 42. Weiss L, Si-Mohamed A, Giral P, Castiel P, Ledur A, Blondin C, Kazatchkine M D, Haeffner-Cavaillon N. J Infect Dis. 1997;176:1621–1624.[PubMed]
  • 43. McKenzie S W, Dallalio G, North M, Frame P, Means R T. AIDS. 1996;10:F29–33.[PubMed]
  • 44. Krowka J F, Gesner M L, Ascher M S, Sheppard H W. Clin Immunol Immunopathol. 1997;85:21–27.[PubMed]
  • 45. Kakkanaiah V N, Ojo-Amaize E A, Peter J B. Clin Diag Lab Immunol. 1998;5:499–502.
  • 46. Polo S, Veglia F, Malnati M S, Gobbi C, Farci P, Raiteri R, Sinicco A, Lusso P. AIDS. 1999;13:447–454.[PubMed]
  • 47. Dolei A, Biolchini A, Serra C, Curreli S, Gomes E, Dianzani F. AIDS. 1998;12:183–190.[PubMed]
  • 48. Gordon C J, Muesing M A, Proudfoot A E, Power C A, Moore J P, Trkola A. J Virol. 1999;73:684–694.
  • 49. Castro K G, Ward J W, Slutsker L, Buehler J W, Jaffe H W, Berkelman R L, Curran J W. MMWR Morb Mortal Wkly Rep. 1992;41:1.[PubMed]
  • 50. Derdeyn C A, Costello C, Kilby J M, Sfakianos G, Saag M S, Kaslow R, Bucy R P. AIDS Res Hum Retroviruses. 1999;15:1063–1071.[PubMed]
  • 51. Conlon K, Llyod A, Chattopadhyay U, Lukacs N, Kunkel S, Schall T, Taub D, Morimoto C, Osborne J, Oppenheim J, et al Eur J Immunol. 1995;25:751–756.[PubMed][Google Scholar]
  • 52. Wagner L, Yang O O, Garcia-Zepeda E A, Ge Y, Kalams S A, Walker B D, Pasternack M S, Luster A D. Nature (London) 1998;391:908–911.[PubMed]
  • 53. Premack B, Schall T. Nat Med. 1996;2:1174–1178.[PubMed]
  • 54. Scarlatti G, Tresoldi E, Bjorndal A, Fredriksson R, Colognesi C, Deng H K, Malnati M S, Plebani A, Siccardi A G, Littman D R, et al Nat Med. 1997;3:1259–1265.[PubMed][Google Scholar]
  • 55. Jansson M, Popovic M, Karlsson A, Cocchi F, Rossi P, Albert J, Wigzell H. Proc Natl Acad Sci USA. 1996;93:15382–15387.
  • 56. Tersmette M, Gruters R A, deWolf F, DeGoede R E Y, Lange J M A, Schellekens P T A, Goudsmit J, Huisman J G, Miedema F. J Virol. 1989;63:2118–2125.
  • 57. Pal R, Garzino-Demo A, Markham P D, Burns J, Brown M, Gallo R C, DeVico A L. Science. 1997;278:695–698.[PubMed]
  • 58. Levy J A, Mackewicz C E, Barker E. Immunol Today. 1996;17:217–224.[PubMed]
  • 59. Lacey S F, McDanal C B, Horuk R, Greenberg M L. Proc Natl Acad Sci USA. 1997;94:9842–9847.
  • 60. Klinger M H, Wilhelm D, Bubel S, Sticherling M, Schroder J M, Kuhnel W. Int Arch Allergy Immunol. 1995;107:541–546.[PubMed]
  • 61. Kameyoshi Y, Dorschner A, Mallet A I, Christophers E, Schroder J M. J Exp Med. 1992;176:587–592.
  • 62. Kinter A, Catanzaro A, Monaco J, Ruiz M, Justement J, Moir S, Arthos J, Oliva A, Ehler L, Mizell S, et al Proc Natl Acad Sci USA. 1998;95:11880–11885.[Google Scholar]
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