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. 1997 Feb;71(2):1227–1236. doi: 10.1128/jvi.71.2.1227-1236.1997

Early cytokine and chemokine gene expression in lymph nodes of macaques infected with simian immunodeficiency virus is predictive of disease outcome and vaccine efficacy.

W Zou 1, A A Lackner 1, M Simon 1, I Durand-Gasselin 1, P Galanaud 1, R C Desrosiers 1, D Emilie 1
PMCID: PMC191177  PMID: 8995646

Abstract

Competitive PCR was used to evaluate the expression of cytokine, granzyme B, and chemokine genes in lymph nodes of macaques recently infected with the simian immunodeficiency virus (SIV) pathogenic molecular clone SIVmac239 (n = 16), the nonpathogenic vaccine strain SIVmac239 delta nef (n = 8), and the nonpathogenic molecular clone SIVmac1A11 (n = 8). For both SIVmac239 and its nef-deleted derivative, strong expression was observed as early as 7 days postinfection for interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha, gamma interferon, and IL-13. The levels of gene induction were equally intense for both viruses despite a lower viral load for SIVmac239 deltanef compared with that for SIVmac239. However, the nature of the cytokine network activation varied with the viral inocula. Primary infection with SIVmac239 was characterized by a higher level of IL-4, IL-10, MIP-1alpha, MIP-1beta, MCP-1, and RANTES gene expression and a lower level of IL-12 and granzyme B gene expression compared with infection with SIVmac239 delta nef. Thus, infection with nef-deleted SIV was associated with a preferential Th1 versus Th2 pattern of cytokine production. Infection with SIVmac1A11 was characterized by a delayed immune response for all markers tested. The unique patterns of cytokine and chemokine gene expression in lymph nodes correlated nicely with the pathogenic potential of the SIV strains used as well as with differences in their ability to serve as protective vaccines.

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Selected References

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  1. Baur A. S., Sawai E. T., Dazin P., Fantl W. J., Cheng-Mayer C., Peterlin B. M. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity. 1994 Aug;1(5):373–384. doi: 10.1016/1074-7613(94)90068-x. [DOI] [PubMed] [Google Scholar]
  2. Benveniste O., Vaslin B., Le Grand R., Cheret A., Matheux F., Theodoro F., Cranage M. P., Dormont D. Comparative interleukin (IL-2)/interferon IFN-gamma and IL-4/IL-10 responses during acute infection of macaques inoculated with attenuated nef-truncated or pathogenic SICmac251 virus. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3658–3663. doi: 10.1073/pnas.93.8.3658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Benveniste O., Vaslin B., Le Grand R., Fouchet P., Omessa V., Theodoro F., Fretier P., Clayette P., Boussin F., Dormont D. Interleukin 1 beta, interleukin 6, tumor necrosis factor alpha, and interleukin 10 responses in peripheral blood mononuclear cells of cynomolgus macaques during acute infection with SIVmac251. AIDS Res Hum Retroviruses. 1996 Feb 10;12(3):241–250. doi: 10.1089/aid.1996.12.241. [DOI] [PubMed] [Google Scholar]
  4. Blauvelt A., Chougnet C., Shearer G. M., Katz S. I. Modulation of T cell responses to recall antigens presented by Langerhans cells in HIV-discordant identical twins by anti-interleukin (IL)-10 antibodies and IL-12. J Clin Invest. 1996 Mar 15;97(6):1550–1555. doi: 10.1172/JCI118578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Bouaboula M., Legoux P., Pességué B., Delpech B., Dumont X., Piechaczyk M., Casellas P., Shire D. Standardization of mRNA titration using a polymerase chain reaction method involving co-amplification with a multispecific internal control. J Biol Chem. 1992 Oct 25;267(30):21830–21838. [PubMed] [Google Scholar]
  7. Canque B., Rosenzwajg M., Gey A., Tartour E., Fridman W. H., Gluckman J. C. Macrophage inflammatory protein-1alpha is induced by human immunodeficiency virus infection of monocyte-derived macrophages. Blood. 1996 Mar 1;87(5):2011–2019. [PubMed] [Google Scholar]
  8. Chakrabarti L., Cumont M. C., Montagnier L., Hurtrel B. Variable course of primary simian immunodeficiency virus infection in lymph nodes: relation to disease progression. J Virol. 1994 Oct;68(10):6634–6643. doi: 10.1128/jvi.68.10.6634-6643.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen Z. W., Kou Z. C., Lekutis C., Shen L., Zhou D., Halloran M., Li J., Sodroski J., Lee-Parritz D., Letvin N. L. T cell receptor V beta repertoire in an acute infection of rhesus monkeys with simian immunodeficiency viruses and a chimeric simian-human immunodeficiency virus. J Exp Med. 1995 Jul 1;182(1):21–31. doi: 10.1084/jem.182.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chensue S. W., Ruth J. H., Warmington K., Lincoln P., Kunkel S. L. In vivo regulation of macrophage IL-12 production during type 1 and type 2 cytokine-mediated granuloma formation. J Immunol. 1995 Oct 1;155(7):3546–3551. [PubMed] [Google Scholar]
  11. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [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. Clerici M., Wynn T. A., Berzofsky J. A., Blatt S. P., Hendrix C. W., Sher A., Coffman R. L., Shearer G. M. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest. 1994 Feb;93(2):768–775. doi: 10.1172/JCI117031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
  16. Collette Y., Chang H. L., Cerdan C., Chambost H., Algarte M., Mawas C., Imbert J., Burny A., Olive D. Specific Th1 cytokine down-regulation associated with primary clinically derived human immunodeficiency virus type 1 Nef gene-induced expression. J Immunol. 1996 Jan 1;156(1):360–370. [PubMed] [Google Scholar]
  17. Daniel M. D., Kirchhoff F., Czajak S. C., Sehgal P. K., Desrosiers R. C. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science. 1992 Dec 18;258(5090):1938–1941. doi: 10.1126/science.1470917. [DOI] [PubMed] [Google Scholar]
  18. Desrosiers R. C., Wyand M. S., Kodama T., Ringler D. J., Arthur L. O., Sehgal P. K., Letvin N. L., King N. W., Daniel M. D. Vaccine protection against simian immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6353–6357. doi: 10.1073/pnas.86.16.6353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Devergne O., Peuchmaur M., Crevon M. C., Trapani J. A., Maillot M. C., Galanaud P., Emilie D. Activation of cytotoxic cells in hyperplastic lymph nodes from HIV-infected patients. AIDS. 1991 Sep;5(9):1071–1079. doi: 10.1097/00002030-199109000-00002. [DOI] [PubMed] [Google Scholar]
  20. Du Z., Ilyinskii P. O., Sasseville V. G., Newstein M., Lackner A. A., Desrosiers R. C. Requirements for lymphocyte activation by unusual strains of simian immunodeficiency virus. J Virol. 1996 Jun;70(6):4157–4161. doi: 10.1128/jvi.70.6.4157-4161.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Du Z., Lang S. M., Sasseville V. G., Lackner A. A., Ilyinskii P. O., Daniel M. D., Jung J. U., Desrosiers R. C. Identification of a nef allele that causes lymphocyte activation and acute disease in macaque monkeys. Cell. 1995 Aug 25;82(4):665–674. doi: 10.1016/0092-8674(95)90038-1. [DOI] [PubMed] [Google Scholar]
  22. Emilie D., Fior R., Llorente L., Marfaing-Koka A., Peuchmaur M., Devergne O., Jarrousse B., Wijdenes J., Boue F., Galanaud P. Cytokines from lymphoid organs of HIV-infected patients: production and role in the immune disequilibrium of the disease and in the development of B lymphomas. Immunol Rev. 1994 Aug;140:5–34. doi: 10.1111/j.1600-065x.1994.tb00863.x. [DOI] [PubMed] [Google Scholar]
  23. Emilie D., Peuchmaur M., Maillot M. C., Crevon M. C., Brousse N., Delfraissy J. F., Dormont J., Galanaud P. Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes. J Clin Invest. 1990 Jul;86(1):148–159. doi: 10.1172/JCI114678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Estaquier J., Idziorek T., Zou W., Emilie D., Farber C. M., Bourez J. M., Ameisen J. C. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med. 1995 Dec 1;182(6):1759–1767. doi: 10.1084/jem.182.6.1759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fan J., Bass H. Z., Fahey J. L. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J Immunol. 1993 Nov 1;151(9):5031–5040. [PubMed] [Google Scholar]
  26. Gallimore A., Cranage M., Cook N., Almond N., Bootman J., Rud E., Silvera P., Dennis M., Corcoran T., Stott J. Early suppression of SIV replication by CD8+ nef-specific cytotoxic T cells in vaccinated macaques. Nat Med. 1995 Nov;1(11):1167–1173. doi: 10.1038/nm1195-1167. [DOI] [PubMed] [Google Scholar]
  27. Gibbs J. S., Lackner A. A., Lang S. M., Simon M. A., Sehgal P. K., Daniel M. D., Desrosiers R. C. Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995 Apr;69(4):2378–2383. doi: 10.1128/jvi.69.4.2378-2383.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Graziosi C., Gantt K. R., Vaccarezza M., Demarest J. F., Daucher M., Saag M. S., Shaw G. M., Quinn T. C., Cohen O. J., Welbon C. C. Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4386–4391. doi: 10.1073/pnas.93.9.4386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Graziosi C., Pantaleo G., Gantt K. R., Fortin J. P., Demarest J. F., Cohen O. J., Sékaly R. P., Fauci A. S. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248–252. doi: 10.1126/science.8023143. [DOI] [PubMed] [Google Scholar]
  30. Ilyinskii P. O., Daniel M. D., Simon M. A., Lackner A. A., Desrosiers R. C. The role of upstream U3 sequences in the pathogenesis of simian immunodeficiency virus-induced AIDS in rhesus monkeys. J Virol. 1994 Sep;68(9):5933–5944. doi: 10.1128/jvi.68.9.5933-5944.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kestler H. W., 3rd, Ringler D. J., Mori K., Panicali D. L., Sehgal P. K., Daniel M. D., Desrosiers R. C. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651–662. doi: 10.1016/0092-8674(91)90097-i. [DOI] [PubMed] [Google Scholar]
  32. Kestler H., Kodama T., Ringler D., Marthas M., Pedersen N., Lackner A., Regier D., Sehgal P., Daniel M., King N. Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science. 1990 Jun 1;248(4959):1109–1112. doi: 10.1126/science.2160735. [DOI] [PubMed] [Google Scholar]
  33. Lackner A. A., Vogel P., Ramos R. A., Kluge J. D., Marthas M. Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus. Am J Pathol. 1994 Aug;145(2):428–439. [PMC free article] [PubMed] [Google Scholar]
  34. Levy J. A., Mackewicz C. E., Barker E. Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells. Immunol Today. 1996 May;17(5):217–224. doi: 10.1016/0167-5699(96)10011-6. [DOI] [PubMed] [Google Scholar]
  35. Lohman B. L., McChesney M. B., Miller C. J., McGowan E., Joye S. M., Van Rompay K. K., Reay E., Antipa L., Pedersen N. C., Marthas M. L. A partially attenuated simian immunodeficiency virus induces host immunity that correlates with resistance to pathogenic virus challenge. J Virol. 1994 Nov;68(11):7021–7029. doi: 10.1128/jvi.68.11.7021-7029.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Luciw P. A., Shaw K. E., Unger R. E., Planelles V., Stout M. W., Lackner J. E., Pratt-Lowe E., Leung N. J., Banapour B., Marthas M. L. Genetic and biological comparisons of pathogenic and nonpathogenic molecular clones of simian immunodeficiency virus (SIVmac). AIDS Res Hum Retroviruses. 1992 Mar;8(3):395–402. doi: 10.1089/aid.1992.8.395. [DOI] [PubMed] [Google Scholar]
  37. Maggi E., Mazzetti M., Ravina A., Annunziato F., de Carli M., Piccinni M. P., Manetti R., Carbonari M., Pesce A. M., del Prete G. Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science. 1994 Jul 8;265(5169):244–248. doi: 10.1126/science.8023142. [DOI] [PubMed] [Google Scholar]
  38. Marfaing-Koka A., Maravic M., Humbert M., Galanaud P., Emilie D. Contrasting effects of IL-4, IL-10 and corticosteroids on RANTES production by human monocytes. Int Immunol. 1996 Oct;8(10):1587–1594. doi: 10.1093/intimm/8.10.1587. [DOI] [PubMed] [Google Scholar]
  39. Marthas M. L., Banapour B., Sutjipto S., Siegel M. E., Marx P. A., Gardner M. B., Pedersen N. C., Luciw P. A. Rhesus macaques inoculated with molecularly cloned simian immunodeficiency virus. J Med Primatol. 1989;18(3-4):311–319. [PubMed] [Google Scholar]
  40. Marthas M. L., Miller C. J., Sutjipto S., Higgins J., Torten J., Lohman B. L., Unger R. E., Ramos R. A., Kiyono H., McGhee J. R. Efficacy of live-attenuated and whole-inactivated simian immunodeficiency virus vaccines against vaginal challenge with virulent SIV. J Med Primatol. 1992 Feb-May;21(2-3):99–107. [PubMed] [Google Scholar]
  41. Marthas M. L., Ramos R. A., Lohman B. L., Van Rompay K. K., Unger R. E., Miller C. J., Banapour B., Pedersen N. C., Luciw P. A. Viral determinants of simian immunodeficiency virus (SIV) virulence in rhesus macaques assessed by using attenuated and pathogenic molecular clones of SIVmac. J Virol. 1993 Oct;67(10):6047–6055. doi: 10.1128/jvi.67.10.6047-6055.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Marthas M. L., Sutjipto S., Higgins J., Lohman B., Torten J., Luciw P. A., Marx P. A., Pedersen N. C. Immunization with a live, attenuated simian immunodeficiency virus (SIV) prevents early disease but not infection in rhesus macaques challenged with pathogenic SIV. J Virol. 1990 Aug;64(8):3694–3700. doi: 10.1128/jvi.64.8.3694-3700.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Miller C. J., Alexander N. J., Sutjipto S., Lackner A. A., Gettie A., Hendrickx A. G., Lowenstine L. J., Jennings M., Marx P. A. Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus. J Virol. 1989 Oct;63(10):4277–4284. doi: 10.1128/jvi.63.10.4277-4284.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Montaner L. J., Gordon S. TH2 downregulation of macrophage HIV-1 replication. Science. 1995 Jan 27;267(5197):538–539. doi: 10.1126/science.7824955. [DOI] [PubMed] [Google Scholar]
  45. Paganin C., Frank I., Trinchieri G. Priming for high interferon-gamma production induced by interleukin-12 in both CD4+ and CD8+ T cell clones from HIV-infected patients. J Clin Invest. 1995 Sep;96(3):1677–1682. doi: 10.1172/JCI118209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pantaleo G., Demarest J. F., Soudeyns H., Graziosi C., Denis F., Adelsberger J. W., Borrow P., Saag M. S., Shaw G. M., Sekaly R. P. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature. 1994 Aug 11;370(6489):463–467. doi: 10.1038/370463a0. [DOI] [PubMed] [Google Scholar]
  47. Pizzolo G., Vinante F., Morosato L., Nadali G., Chilosi M., Gandini G., Sinicco A., Raiteri R., Semenzato G., Stein H. High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS. AIDS. 1994 Jun;8(6):741–745. doi: 10.1097/00002030-199406000-00003. [DOI] [PubMed] [Google Scholar]
  48. Reimann K. A., Tenner-Racz K., Racz P., Montefiori D. C., Yasutomi Y., Lin W., Ransil B. J., Letvin N. L. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol. 1994 Apr;68(4):2362–2370. doi: 10.1128/jvi.68.4.2362-2370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Romagnani S., Del Prete G., Manetti R., Ravina A., Annunziato F., De Carli M., Mazzetti M., Piccinni M. P., D'Elios M. M., Parronchi P. Role of TH1/TH2 cytokines in HIV infection. Immunol Rev. 1994 Aug;140:73–92. doi: 10.1111/j.1600-065x.1994.tb00865.x. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Sasseville V. G., Du Z., Chalifoux L. V., Pauley D. R., Young H. L., Sehgal P. K., Desrosiers R. C., Lackner A. A. Induction of lymphocyte proliferation and severe gastrointestinal disease in macaques by a nef gene variant SIVmac239. Am J Pathol. 1996 Jul;149(1):163–176. [PMC free article] [PubMed] [Google Scholar]
  52. Skowronski J., Parks D., Mariani R. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. EMBO J. 1993 Feb;12(2):703–713. doi: 10.1002/j.1460-2075.1993.tb05704.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Smith M. O., Heyes M. P., Lackner A. A. Early intrathecal events in rhesus macaques (Macaca mulatta) infected with pathogenic or nonpathogenic molecular clones of simian immunodeficiency virus. Lab Invest. 1995 May;72(5):547–558. [PubMed] [Google Scholar]
  54. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994 Dec 15;84(12):4008–4027. [PubMed] [Google Scholar]
  55. Zou W., Durand-Gasselin I., Dulioust A., Maillot M. C., Galanaud P., Emilie D. Quantification of cytokine gene expression by competitive PCR using a colorimetric assay. Eur Cytokine Netw. 1995 Jul-Dec;6(4):257–264. [PubMed] [Google Scholar]
  56. von Herrath M., Oldstone M. B., Fox H. S. Simian immunodeficiency virus (SIV)-specific CTL in cerebrospinal fluid and brains of SIV-infected rhesus macaques. J Immunol. 1995 May 15;154(10):5582–5589. [PubMed] [Google Scholar]

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