The progression of HIV-infected subjects to AIDS was recently postulated to be controlled by the balance between type 1 cytokines (mainly enhancing cell-mediated immunity) and type 2 cytokines (mainly augmenting antibody production). Thus, progression of HIV infection was suggested to be accompanied by a decline of in vitro production of interleukin-2 (IL-2), IL-12 and interferon gamma (IFN-γ) (type 1 cytokines) and an increase in the production of IL-4, IL-5, IL-6 and IL-10 (type 2 cytokines) by peripheral blood mononuclear cells of HIV-seropositive patients. According to this hypothesis, clinical markers of progression would be considered the loss of the ability to elicit a delayed-type hypersensitivity reaction to ubiquitous antigens (secondary to defective IL-2 production), hyper-lgE (secondary to increased IL-4 production) and hypereosynophilia (secondary to increased IL-5 production). The type 1 to type 2 shift was suggested to be predictive for the following events: (i) reduction in CD4 counts; (ii..

Daria Trabattoni

Donatella Arienti

Mara Biasin

Maria Luisa Fusi

Maria Luisa Villa

Mario Clerici

Stefania Piconi

Stefania Ruzzante

English

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Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=iann20Download by: [Universite Laval] Date: 03 April 2016, At: 21:06Annals of MedicineISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20Type 1 and Type 2 Cytokines in HIV Infection– A Possible Role in Apoptosis and DiseaseProgressionMario Clerici, Maria Luisa Fusi, Stefania Ruzzante, Stefania Piconi, MaraBiasin, Donatella Arienti, Daria Trabattoni & Maria Luisa VillaTo cite this article: Mario Clerici, Maria Luisa Fusi, Stefania Ruzzante, Stefania Piconi, MaraBiasin, Donatella Arienti, Daria Trabattoni & Maria Luisa Villa (1997) Type 1 and Type 2Cytokines in HIV Infection – A Possible Role in Apoptosis and Disease Progression, Annals ofMedicine, 29:3, 185-188, DOI: 10.3109/07853899708999334To link to this article:  http://dx.doi.org/10.3109/07853899708999334Published online: 08 Jul 2009.Submit your article to this journal Article views: 24View related articles Editorial Type 1 and Type 2 Cytokines in HIV Infection - A Possible Role in Apoptosis and Disease Progression Mario Clerici, Maria Luisa Fusi, Stefania Ruzzante, Stefania Piconi', Mara Biasin, Donatella Arienti, Daria Trabattoni and Maria Luisa Villa The progression of HIV-infected subjects to AIDS was recently postulated to be controlled by the balance between type 1 cytokines (mainly enhancing cell-mediated immunity) and type 2 cytokines (mainly augmenting antibody production). Thus, progression of HIV infection was suggested to be accompanied by a decline of in vitro production of interleukin-2 (lL-2), 11-12 and interferon gamma (IFN-y) (type 1 cytokines) and an increase in the production of 11-4, IL-5, IL-6 and IL-10 (type 2 cytokines) by peripheral blood mononuclear cells of HIV-seropositive patients. According to this hypothesis, clinical markers of progression would be considered the loss of the ability to elicit a delayed-type hypersensitivity reaction to ubiquitous antigens (secondary to defective 11-2 production), hyper-lgE (secondary to increased IL-4 production) and hypereosynophilia (secondary to increased 11-5 production). The type 1 to type 2 shift was suggested to be predictive for the following events: (i) reduction in CD4 counts; (ii) time to AIDS diagnosis; (iii) time to death. Support for this hypothesis stems from the recent observation that a strong type l/weak type 2 cytokine production profile was observed in HIV-seropositive patients with delayed or absent disease progression, whereas progression of HIV infection was characterized by a weak type 1 /strong type 2 cytokine production profile. PBMC of HIV-seropositive individuals are susceptible to antigen-induced cell death (AICD) after antigen recognition via T-cell receptor (TcR). While TcR-induced AICD is seen in CD4' and CD8' cells programmed cell death induced by recall antigens is preferentially observed in CD4' cells, a situation more closely resembling the CD4 depletion of HIV infection. Because type 1 cytokines reduce, whereas type 2 cytokines augment T-lymphocyte AICD, an increase in the concentration of type 2 cytokines could result in the decline in CD4' cells seen in HIV infection. Key words: AIDS; apoptosis; cytokines; disease progression; HIV; immunology. (Annals of Medicine 29: 185-1 88, 1997) Introduction Human immunodeficiency virus (HIV) infection is associ- ated with a profound dysregulation of the immune system (1). Interestingly, functional hyperactivation of humoral immunity (HI) is observed in patients showing From the Cattedra di Immunologia, Universita degli Studi di Milano, Padiglione LITA, Ospedale L. Sacco, Milano; and 'la Divisione di Malattie Infettive, Ospedale L. Sacco, Milano, Italy. Address and reprint requests: Mario Clerici, MD, Cattedra di Immunologia, Universita degli Studi di Milano, Via Venezian, 1, 1-20133 Milano, Italy. Fax: +39 2 3821 0350, E-mail: maao@imiucca.csi.unimi.it. signs * of defective cell-mediated immunity (CMI) (1). Thus, hypergammaglubulinaemia with hypereosinophilia and hyper-lgE are associated with impaired delayed- type hypersensitivity (DTH) reactions to common recall antigens (2, 3). Because different cytokines are known to stimulate mainly either CMI or HI (type 1 and type 2 cytokines, respectively) (2, 3), cytokine production by peripheral blood mononuclear cells (PBMC) of HIV- seropositive individuals was analysed. The results sug- gested that type 1 cytokine production is defective and type 2 cytokine production is enhanced in HIV- seropositive individuals, and that the degree of this dis- equilibrium might be predictive for progression of HIV infection to the acquired immunodeficiency syndrome (AIDS). 0 1997 The Finnish Medical Society DUODECIM, Ann Med 29,185-1 88 Downloaded by [Universite Laval] at 21:06 03 April 2016 186 Clerici et al. Type 1 and Type 2 Cytokines in the Progression of HIV Infection T-helper (TH) lymphocytes have been functionally divided into two subsets based on the cytokines they produce; these subsets are named T-helper 1 and T-helper 2 (TH1 and TH2) (4, 5). Because cytokines are produced by cell types other than T lymphocytes a functional definition was introduced; thus, type 1 cytokines mainly stimulate CMI whereas type 2 cytokines mainly stimulate HI. IL-2, IL-12, IFN-7 and probably IL-15 are type 1 cytokines; IL-4, IL-5, IL-6, IL-10 and IL-13 are type 2 cytokines (2, 3). Defective antigen- and mitogen-stimulated IL-2 production has been described in HIV infection since 1985 (6, 7). Analyses of defective IL-2 production have shown that subtle and complex defects in TH function can be detected independently of a decline in CD4 counts, and before the onset of symptoms (7). Thus, when PBMC of asymptomatic HIV-seropositive individuals are stimu- lated in vitro with recall antigens, HLA alloantigens and mitogens, and IL-2 production is measured, different degrees of impairment in TH function are observed. To summarize: (i) IL-2 can be produced in response to all antigens; (ii) recall antigen-stimulated IL-2 production can be selectively defective; (iii) only phytohaemagglu- tinin (PHA)-stimulated IL-2 production can be observed; and (iv) the ability to produce IL-2 can be completely lost (2, 3). Approximately two-thirds of HIV-seropositive asymptomatic individuals show one or more of these TH functional defects without exhibiting a critical reduction in the number of CD4' T lymphocytes. These different degrees of impairment in IL-2 production are secondary to the different antigen-presenting cell-TH cell inter- actions required for the diverse antigens (2, 3), and are predictive for the following: (i) rate of decline in the number of CD4' T lymphocytes; (ii) time to diagnosis of AIDS; and (iii) time to death (8, 9). Therefore, defects in IL-2 production are predictive for three clinically relevant end-points in HIV infection and progression to AIDS (8, 9). Because in HIV infection IL-2 production is defective (and IL-2 mainly stimulates CMI) and HI is abnormally activated and because different cytokines stimulate CMI or HI, a number of laboratories examined type 1 and type 2 cytokine production by PBMC of HIV- seropositive individuals. The results observed in some laboratories suggested that, beside IL-2, IL-12 is also severely defective in HIV infection (IFN-y has been reported by different groups to be either defective or augmented) (2, 3), whereas the production of type 2 cytokines IL-4, IL-5, IL-6 and IL-10 is enhanced (2, 3). Because different cytokines are responsible for diverse biological effects, the concentration of IgE (IL-4 driven) and eosinophils (IL-5 driven) was analysed in HIV- seropositive individuals. As expected, hyper-lgE (2, 3) and hypereosinophilia (2, 3) were detected in those patients in whom defective (IL-2, IL-12 and IFN-y driven) DTH to common recall antigens is present (2, 3). Additionally, hyper-lgE and hypereosinophilia were recognized as predictors of poor prognosis in HIV- seropositive individuals. These data led to the formula- tion of the hypothesis that a type 1 to type 2 cytokine shift is present in HIV infection. This hypothesis was met initially by some critiques, the most relevant of which was raised by Dr Fauci's group, who analysed cytokine production in unstimulated PBMC of HIV-seropositive individuals by polymerase chain reaction and could not observe such a shift (lo), but has recently been widely accepted. Corollary to the hypothesis is the prediction that strong type 1 cytokine production and well- preserved CMI would correlate with lack of disease progression. Because HIV infection can result in different clinical outcomes (1 l), markers of progression and protection were analysed in HIV-seropositive individuals pro- gressing toward AIDS and in the minority of those patients, defined long-term nonprogressors (LTNP), who do not show signs of disease and maintain stable CD4 counts, despite a long-lasting HIV infection. Type 1 and type 2 cytokine production was examined in paediatric and adult cohorts to analyse similarities and differences between vertically transmitted and adult-acquired HIV infection. In both cohorts data obtained in two groups of individuals were compared: (i) asymptomatic HIV- seropositive individuals infected for more than 8 years with a CD4 count more than 500 pL; and (ii) patients with progressive HIV infection as indicated by presence of symptomatology; and/or CD4 counts less than 450 pL. Both in adult-acquired and vertically transmitted infection type 1 cytokine production was observed to be significantly augmented and type 2 cytokine production significantly reduced in HIV-seropositive LTNP indivi- duals compared to HIV-seropositive individuals with progressive HIV infection (12, 13). Therefore, cytokine production profiles by in vitro PHA-stimulated PBMC can distinguish between HIV-seropositive patients with different patterns of disease progression, in that a type 1 predominance is evident in LTNP patients whereas a type 2 predominance is characteristic of patients with progressive HIV infection. Finally, because the isolation of syncytium-inducing (SI) HIV variants is associated with disease progression (1 4), the possible correlation between a type 1 to type 2 shift and isolation of these variants was analysed. Recent results show that isola- tion of SI variants was indeed associated with the weakest type 1 cytokine production, the strongest type 2 cytokine production and the lowest CD4 counts in both adult and paediatric groups of HIV-seropositive patients (1 5). Thus, the virological and immunological correlates of disease protection and progression are associated variables that define two different subsets of HIV-seropositive individuals. Cytokines and Apoptosis in HIV Infection The proposed shift in type 1 and type 2 cytokine production could be directly responsible for the reduc- tion of CD4 counts which is the hallmark of HIV infec- 0 1997 The Finnish Medical Society DUODECIM, Ann Med 29, 185-188 Downloaded by [Universite Laval] at 21:06 03 April 2016 Immunology of HIV Infection 187 tion. Thus, after antigen recognition via their T-cell receptor (TcR), HIV T lymphocytes can either classically become activated and proliferate or can undergo antigen-induced cell death (AICD) in vitro. Lymphocytes of HIV-seropositive patients are particularly susceptible to TcR-induced AlCD (16), and the extent of this AlCD can be differentially modulated in vitro by type 1 and type 2 cytokines (17, 18). Thus, type 1 cytokines reduce T-lymphocyte AICD; in contrast, type 2 cytokines have either no effect or enhance in vitro T-cell AlCD (17). Additionally, AlCD can be inhibited by antibodies against IL-4 and IL-10, and enhanced by anti-IL-12 (17). Selective stimulation of CD4+ lymphocytes by recall antigens, including peptides of the envelope of HIV, was recently described to induce AlCD exclusively in the CD4 subset, a situation that more closely resembles that observed in vivo (17). Even in this scenario, AlCD was oppositely modulated by type 1 and type 2 cytokines, or by the neutralization of type 1 or type 2 cytokines (17). AlCD was verified to be effected by lymphotoxin; lymphotoxin was also found to be respon- sible for a soluble-factor-mediated amplifying loop which causes AlCD in innocent-bystander lymphocytes (17). Thus, impaired production of type 1 cytokines and augmented generation of type 2 cytokines characteristic of HIV infection could contribute to the destruction of CD4 lymphocytes; this destruction would be mediated by lymphotoxin. Briefly, antigen stimulation of lympho- cytes of HIV-seropositive individuals in the presence of abnormally low concentrations of IFN-y, IL-2 and IL-12, and/or of abnormally elevated concentrations of IL-4 and IL-10, would result in the induction of AlCD instead of in the induction of T-cell proliferation. This aberrant process could contribute to the progressive decline of CD4' T lymphocytes observed in HIV infection. It is important to conclude this part by underlying the facts that: (if this intriguing hypothesis is based on in vitro observations; and (ii) direct HIV-dependent cytopathy has an undeniable role in the killing of HIV-infected CD4 lymphocytes. Conclusions The data summarized in this brief review underline the role of the immune response in controlling the progres- sion of HIV infection to AIDS, and the pivotal role of the qualitative and quantitative defects of the immune system in the pathogenesis of this disease. Because of the importance of the immune response in controlling HIV, we believe that antiretroviral therapies will not successfully eradicate HIV and that HIV-seropositive patients will not be ultimately cured unless therapies aimed at restoring the immune system are associated with the antiretroviral drugs currently employed. Thank- fully, a number of different immunomodulators are currently being examined in small clinical trials. This paper was supported by grants from lstituto Superiore di Sanita 'Vlll Progetto AIDS 1995 n. 9304-40. We thank Gene M. Shearer, PhD (Experimental Immunology Branch, NCI, NIH, Bethesda, MD, USA) for continuous friendship and support. We are grateful to Prof. Mauro Moroni, Prof. Massimo Galli and Dr Claudia Balotta (Clinica delle Malattie Infettive, H. L. Sacco, Universita di Milano) as well as Prof. Nicola Principi and Dr Alessandra Vigano (Cattedra di Pediatria IV, H. L. Sacco, Universita di Milano) for the indispensable and continuous collaboration. References 1. Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 1993; 57: 183-233. 2. Clerici M, Shearer GM. Is HIV associated with a TH1 +TH2 switch? lmmunol Today 1993; 14: 107-1 1. 3. Clerici M, Shearer GM. The THl /TH2 model of HIV infec- tion: new insights. lmmunol Today 1994; 15: 575-81. 4. Mosmann TR, Coffman RI. Two types of mouse T helper cell clone: implication for immune regulation. lmmunol Today 1987; 8: 223-6. 5. Mosmann TR, Coffman RI. TH1 and TH2 cells: different pattern of lymphokine secretion lead to different functional properties. Annu Rev lmmunoll989; 7: 145-68. 6. Lane HC, Depper JM, Greene WC, et al. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome: evidence for a selective defect in soluble antigens recognition. N Engl J Med 1985; 7. Miedema F, Petit AJ, Terpstra FG, et al. Immunological abnormalities in human immunodeficiency virus (HIV)- infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. J Clin lnvest 1988; 82: 1908-16. 8. Lucey DR, Melchers GP, Hendrix CW, et al. The US Air Force HIV study 1985-1 990: immunological analyses, seroconversion and the potential utility of a T helper functional assay to predict change in CD4+ T-cell counts during early stages of HIV infection. J lnfect Dis 1991; 164: 9. Dolan MJ, Blatt SP, Hendrix CW, et al. In vitro T cell function, delayed type hypersensitivity skin testing, and CD4 T cell subset phenotyping independently predict survival time in patients infected with human immuno- deficiency virus. J lnfect Dis 1995; 172: 79-87. 10. Graziosi C, Pantaleo G, Gantt KR, et al. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV infected individuals. Science 1992; 265: 248-52. 11. Levy JA. HIV pathogenesis and long-term survival. AlDS 12. Vigano A, Principi N, Villa ML, et ai. Immunologic charac- terization of children vertically infected with human immunodeficiency virus, with slow or rapid disease progression. J fediatr 1995; 126: 368-74. 13. Tersmette M, De Goede REY, Al BJM, et al. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired imunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol 1988; 14. Koot, M. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann lntern Med 1993; 11 8: 681 -8. 15. Clerici M, Balotta C, Salvaggio A, et al. HIV phenotype and interleukin-2/interleukin-lO ratio are associated markers of protection and progression in HIV infection. Blood (in press). 16. Ameisen JC, Capron A. Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. lmmunol 313: 79-84. 631 -7. 1993; 7: 1401-10. 62: 2026-32. Today 1991; 12: 102-6. 0 1997 The Finnish Medical Society DUODECIM, Ann Med 29, 185-188 Downloaded by [Universite Laval] at 21:06 03 April 2016 188 Clerici et al. 17. Clerici M, Sarin A, Coffman RL, et al. Type l l type 2 cytokine modulation of T cell programmed cell death as a model for HIV pathogenesis. Proc Natl Acad Sci USA 1994; 91: 11811-5. 18. Adachi Y, Oyazu N, Than S, McCloskey W, Pahwa S. IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down-modulation of Bcl-2. J lmmunol 1996; 157: 4184-93. 0 1997 The Finnish Medical Society DUODECIM, Ann Med 29, 185-188 Downloaded by [Universite Laval] at 21:06 03 April 2016 

Type 1 and Type 2 Cytokines in HIV Infection – A Possible Role in Apoptosis and Disease Progression

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Type 1 and Type 2 Cytokines in HIV Infection – A Possible Role in Apoptosis and Disease Progression

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