Abstract
Comparison of immune responses to infection by a pathogenic or a nonpathogenic immunodeficiency virus in macaques may provide insights into pathogenetic events leading to simian AIDS. This work is aimed at exploring cytokine expression during infection by simian immunodeficiency virus (SIV). We used semiquantitative reverse transcription-PCR to monitor interleukin (IL)-2/interferon (IFN)-gamma (Th1-like), and IL-4/IL-10 (Th2-like) expression in unmanipulated peripheral blood mononuclear cells (PBMCs), during the acute phase of infection of eight cynomolgus macaques (Macaca fascicularis) with a pathogenic primary isolate of SIVmac251 (full-length nef), and of four other cynomolgus macaques by an attenuated molecular clone of SIVmac251 (nef-truncated). All the monkeys became infected, as clearly shown by the presence of infected PBMCs and by seroconversion. Nevertheless, PBMC-associated virus loads and p27 antigenemia in monkeys infected by the attenuated virus clone remained lower than those observed in animals infected with the pathogenic SIVmac251 isolate. A rise of IL-10 mRNA expression occurred in both groups of monkeys coincident with the peak of viral replication. In monkeys infected with the pathogenic SIVmac251, IL-2, IL-4, and IFN-gamma mRNAs were either weakly detectable or undetectable. On the contrary, animals infected by the attenuated virus exhibited an overexpression of these cytokine mRNAs during the first weeks after inoculation. The lack of expression of these cytokines in monkeys infected with the pathogenic primary isolate may reflect early immunodeficiency.
Full text
PDF![3658](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/53f82575f471/pnas01515-0508.png)
![3659](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/c4183043c17a/pnas01515-0509.png)
![3660](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/fc0045d7a65a/pnas01515-0510.png)
![3661](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/98bea2abaf34/pnas01515-0511.png)
![3662](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/3d3666003c6c/pnas01515-0512.png)
![3663](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4761/39667/bdbe59097342/pnas01515-0513.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Almond N., Jenkins A., Slade A., Heath A., Cranage M., Kitchin P. Population sequence analysis of a simian immunodeficiency virus (32H reisolate of SIVmac251): a virus stock used for international vaccine studies. AIDS Res Hum Retroviruses. 1992 Jan;8(1):77–88. doi: 10.1089/aid.1992.8.77. [DOI] [PubMed] [Google Scholar]
- Ameisen J. C., Estaquier J., Idziorek T. From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation. Immunol Rev. 1994 Dec;142:9–51. doi: 10.1111/j.1600-065x.1994.tb00882.x. [DOI] [PubMed] [Google Scholar]
- Ansari A. A., Mayne A., Hunt D., Sundstrom J. B., Villinger F. TH1/TH2 subset analysis. I. Establishment of criteria for subset identification in PBMC samples from nonhuman primates. J Med Primatol. 1994 Feb-May;23(2-3):102–107. doi: 10.1111/j.1600-0684.1994.tb00109.x. [DOI] [PubMed] [Google Scholar]
- Baldwin G. C., Fleischmann J., Chung Y., Koyanagi Y., Chen I. S., Golde D. W. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc Natl Acad Sci U S A. 1990 May;87(10):3933–3937. doi: 10.1073/pnas.87.10.3933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Benveniste O., Vaslin B., Villinger F., Le Grand R., Ansari A. A., Dormont D. Cytokine mRNA levels in unmanipulated (ex vivo) and in vitro stimulated monkey PBMCs using a semi-quantitative RT-PCR and high sensitivity fluorescence-based detection strategy. Cytokine. 1996 Jan;8(1):32–41. doi: 10.1006/cyto.1996.0005. [DOI] [PubMed] [Google Scholar]
- Bretscher P. A., Wei G., Menon J. N., Bielefeldt-Ohmann H. Establishment of stable, cell-mediated immunity that makes "susceptible" mice resistant to Leishmania major. Science. 1992 Jul 24;257(5069):539–542. doi: 10.1126/science.1636090. [DOI] [PubMed] [Google Scholar]
- Clerici M., Clark E. A., Polacino P., Axberg I., Kuller L., Casey N. I., Morton W. R., Shearer G. M., Benveniste R. E. T-cell proliferation to subinfectious SIV correlates with lack of infection after challenge of macaques. AIDS. 1994 Oct;8(10):1391–1395. doi: 10.1097/00002030-199410000-00004. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Desrosiers R. C. The simian immunodeficiency viruses. Annu Rev Immunol. 1990;8:557–578. doi: 10.1146/annurev.iy.08.040190.003013. [DOI] [PubMed] [Google Scholar]
- Dittmer U., Lüke W., Stahl-Hennig C., Coulibaly C., Petry H., Bodemer W., Hunsmann G., Voss G. Early helper T-cell dysfunction in simian immunodeficiency virus but not in human immunodeficiency virus type-2-infected macaques. J Med Primatol. 1994 Jul;23(5):298–303. doi: 10.1111/j.1600-0684.1994.tb00287.x. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Israël-Biet D., Cadranel J., Beldjord K., Andrieu J. M., Jeffrey A., Even P. Tumor necrosis factor production in HIV-seropositive subjects. Relationship with lung opportunistic infections and HIV expression in alveolar macrophages. J Immunol. 1991 Jul 15;147(2):490–494. [PubMed] [Google Scholar]
- Le Grand R., Clayette P., Noack O., Vaslin B., Theodoro F., Michel G., Roques P., Dormont D. An animal model for antilentiviral therapy: effect of zidovudine on viral load during acute infection after exposure of macaques to simian immunodeficiency virus. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1279–1287. doi: 10.1089/aid.1994.10.1279. [DOI] [PubMed] [Google Scholar]
- Le Grand R., Vogt G., Vaslin B., Roques P., Théodoro F., Aubertin A. M., Dormont D. Specific and non-specific immunity and protection of macaques against SIV infection. Vaccine. 1992;10(12):873–879. doi: 10.1016/0264-410x(92)90052-l. [DOI] [PubMed] [Google Scholar]
- Maggi E., Biswas P., Del Prete G., Parronchi P., Macchia D., Simonelli C., Emmi L., De Carli M., Tiri A., Ricci M. Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol. 1991 Feb 15;146(4):1169–1174. [PubMed] [Google Scholar]
- 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]
- Miedema F., Meyaard L., Koot M., Klein M. R., Roos M. T., Groenink M., Fouchier R. A., Van't Wout A. B., Tersmette M., Schellekens P. T. Changing virus-host interactions in the course of HIV-1 infection. Immunol Rev. 1994 Aug;140:35–72. doi: 10.1111/j.1600-065x.1994.tb00864.x. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- 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]
- Rud E. W., Cranage M., Yon J., Quirk J., Ogilvie L., Cook N., Webster S., Dennis M., Clarke B. E. Molecular and biological characterization of simian immunodeficiency virus macaque strain 32H proviral clones containing nef size variants. J Gen Virol. 1994 Mar;75(Pt 3):529–543. doi: 10.1099/0022-1317-75-3-529. [DOI] [PubMed] [Google Scholar]
- Sinicco A., Biglino A., Sciandra M., Forno B., Pollono A. M., Raiteri R., Gioannini P. Cytokine network and acute primary HIV-1 infection. AIDS. 1993 Sep;7(9):1167–1172. doi: 10.1097/00002030-199309000-00003. [DOI] [PubMed] [Google Scholar]
- Street N. E., Schumacher J. H., Fong T. A., Bass H., Fiorentino D. F., Leverah J. A., Mosmann T. R. Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990 Mar 1;144(5):1629–1639. [PubMed] [Google Scholar]
- Villinger F., Hunt D., Mayne A., Vuchetich M., Findley H., Ansari A. A. Qualitative and quantitative studies of cytokines synthesized and secreted by non-human primate peripheral blood mononuclear cells. Cytokine. 1993 Sep;5(5):469–479. doi: 10.1016/1043-4666(93)90038-7. [DOI] [PubMed] [Google Scholar]
- Voth R., Rossol S., Klein K., Hess G., Schütt K. H., Schröder H. C., Meyer zum Büschenfelde K. H., Müller W. E. Differential gene expression of IFN-alpha and tumor necrosis factor-alpha in peripheral blood mononuclear cells from patients with AIDS related complex and AIDS. J Immunol. 1990 Feb 1;144(3):970–975. [PubMed] [Google Scholar]
- Zagury J. F., Bernard J., Achour A., Astgen A., Lachgar A., Fall L., Carelli C., Issing W., Mbika J. P., Picard O. Identification of CD4 and major histocompatibility complex functional peptide sites and their homology with oligopeptides from human immunodeficiency virus type 1 glycoprotein gp120: role in AIDS pathogenesis. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7573–7577. doi: 10.1073/pnas.90.16.7573. [DOI] [PMC free article] [PubMed] [Google Scholar]