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Plasticity of lymphoid compartments during HIV infection and treatments: hopes and limits
Microbes and Infection 4 (2002) 575–580 www.elsevier.com/locate/micinf
Forum in Immunology
Plasticity of lymphoid compartments during HIV infection and treatments: hopes and limits Béhazine Combadière, Guislaine Carcelain, Patrice Debré, Brigitte Autran * Laboratoire d’immunologie cellulaire et tissulaire, unité INSERM 543, hôpital Pitié-Salpétrière, 83, boulevard de l’Hôpital, 75013 Paris, France
Abstract Immune reconstitution during antiretroviral therapy has recently been shown to depend upon multiple factors at work in T-cell homeostasis, amongst which the reduction of thymus dysfunction and of immune hyperactivation is instrumental. The restoration of host defenses against opportunistic pathogens is, however, balanced by the poor immunity restored against HIV thus giving a satisfying link between antigen stimulation and the reconstitution of immune responses to pathogens. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: HIV; HAART; Homeostasis; TREC
1. Introduction
2. T-lymphocyte homeostasis
HIV infection induces major disorders in T-cell homeostasis that lead to profound CD4 cell depletion and cause severe immunodeficiencies. Antiretroviral drug regimens combining inhibitors of HIV reverse transcriptase and protease, the so-called “highly active antiretroviral therapy” (HAART), opened in 1995 a new era by inducing major CD4 cell increases, the mechanisms of which have been extensively studied since the first reports of immune restoration in 1997. In addition to the recirculation of sequestered memory T cells, reexpansion of naive CD4 T cells and rediversification of the CD4 T-cell repertoires, thymus production and peripheral homeostasis were shown to play central roles. Meanwhile, the host develops a transient and potent primary and memory cytotoxic response against the virus that cannot stop viral replication. These findings illustrate the plasticity of the lymphoid compartment even after the severe alterations induced by the virus. Limits in the restoration of HIV-specific immunity also illustrate the tight equilibrium existing between virus exposure, antigen stimulation and numbers of specific CD4 T cells and CD8 memory responses.
It is commonly accepted that the numbers of T cells in mice and humans are well controlled. AIDS is a typical example of such tight homeostatic control as patient peripheral T-cell count is a key way of monitoring disease progression. The fact that virus infections increase or decrease lymphocyte counts also reflects the rapid and exponential increment in virus-specific T cells, one of the principal host resources for limiting virus and disease progression. AIDS is again a typical example with the major increase in CD8 cell numbers leading to an inversion of the normal CD4/CD8 cell 2:1 ratios even before the CD4 cells are depleted. Once viruses are cleared or controlled the rapid decay in virus antigen production provokes a parallel decrease in virus-specific T-cell numbers to a quasiequilibrium level which might depend on the intensity of the initial burst but also on other poorly understood mechanisms. Such a decrease, however, is rarely observed in HIV infection where the virus is poorly controlled. In normal individuals, naive T cells once created in the thymus move to the periphery where they will encounter antigen. Once they emerge from the thymus, there is plenty of evidence that the peripheral pool of T lymphocytes increases in young animals [1–3]. In adults, the thymus output can be affected under some circumstances: the activity of the thymus can slightly increase in animals with a severe deficiency in the peripheral T-cell pool. The entering of naive T cells into empty peripheral compart
* Corresponding author. Tel.: +33-1-42-17-74-03; fax: +33-1-42-17-7490. E-mail address: [email protected] (B. Autran). © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. PII: S 1 2 8 6 - 4 5 7 9 ( 0 2 ) 0 1 5 7 5 - 7
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ments induces a cell division process that requires interaction with major histocompatibility complex (MHC) proteins as has been seen in animal models [4–9]. In addition, naive T cells do not divide in mature animals with a “full” T-cell compartment. They seem to require exogenous “survival” signals [10,11] such as cytokines IL-7, IL-4 [12,13] and to a lesser extent IL-6 or interactions between TCR and MHC–self peptide complexes [14–17]. Whatever the method of survival required by naive T cells, their major quest remains the encountering of an antigen. During infection by pathogens, the numbers of activated T cells increase rapidly. This phenomenon is driven by appropriate full TCR engagement and use of costimulatory molecules such as CD28, OX-40, LFA-1 [17]. The TCR engagement induces CD4 and CD8 effector functions and IL-2 production that acts as an autocrine division factor. The peripheral pool can then reach a limited number. Different studies have established that T-cell activation predisposes to antigen-induced mature T-cell apoptosis. The original studies by Lenardo [18] and Janssen et al. [19] explicitly demonstrated, in αβ and γδ T cells, respectively, that a key component of antigen-induced apoptosis is IL-2 stimulation and proliferation prior to lethal TCR engagement. This homeostatic phenomenon again tends to reduce the peripheral pool size. The studies by Hornung et al. [20] and Combadière et al. [21] demonstrated that selective TCR signaling regulates lymphocyte fate in an antigen-specific manner, implying that the elaboration of partial signals by the TCR could promote tolerance by benign selection of activated T cells. The latter phenomenon can occur in activated T lymphocytes and participate in nonselective T-cell elimination during the course of the disease. As discussed later, HIV-specific CD4+ T cells seem to be lost in most patients soon after the primary infection and remain detectable only in individuals with low virus production and a low T-cell activation profile. Homeostatic control mechanisms might also have the untoward complication of allowing the immune response to fail when confronted with a rapidly mutating pathogen such as HIV. Another aspect of T-cell alterations during HIV infection is that increasing proportions of T cells bearing activation markers are thus more sensitive to antigen-induced cell death. The very existence and survival of memory T cells has been contested for many years. Exposure to antigens combined with the presence of adjuvant and with the production of inflammatory cytokines might be related to the rapid conversion of antigen-specific naive T cells to antigenspecific memory T cells. What maintains a high frequency of memory T cells is still unknown. It has been recently shown that chemokines may select various types of memory T-cell populations [22,23]. To some extent, survival of memory T cells is controlled by their location. An additional idea is that continuous and slow cell division of memory cells would maintain them under the influence of cytokines such as IL-15 [24]. This cytokine is highly produced by the host during infections. It has been recently shown that
whereas IL-15 increases the number of CD8 cells, IL-2 decreases it. Once again, such a mechanism of memory T-cell survival might fail when confronted with a rapidly mutating virus such as HIV. Thus, with the coexistence of these phenomena, what are the possibilities of ensuring HIV-specific primary and memory immune responses?
3. The kinetics of CD4 cell reconstitution: a two-phase process Antiretroviral treatment rapidly increases CD4 counts, concurrently with the reduction in plasma virus load. This phenomenon has been suggested to reflect a recirculation of T cells from lymphoid tissues [25–27]. Various studies performed on peripheral blood cells and on lymph nodes confirmed this redistribution hypothesis [28–32], which seems to occur at any stage of CD4 cell depletion [33,34]. Such an early rise in the CD4 cell count was shown to be mainly influenced by the intensity of CD4 depletion at initiation of treatment and by the slope of CD4+ T-cell decline during the year prior to treatment initiation [35]. CD4 cell expansion slows down after the third month of treatment but persists over years of successful antiretroviral therapy until the peripheral CD4 counts reach normal or subnormal values [25,26,32,35–37]. This second phase appears to be strongly correlated with the magnitude of the plasma viral load reduction [35,36] but is not related to CD4 depletion at treatment initiation [35] nor to the stage of the disease [35]. These findings suggest that the immune system has the same capacity to repopulate the CD4 compartment whatever the severity of the defects installed before introduction of HAART. The time required to reach normal or subnormal CD4 values can range from 2 to 6 years depending on the disease stage at which treatment had been initiated [32,34–36]. In some patients, however, the CD4 reconstitution appears to be virus-independent. The absence of a CD4 response can contrast with a major and stable viral load reduction in approximately 5% cases [35]. The latter paradoxical CD4 responses might involve various factors such as age, reflecting some impairment in thymus tissue [35–39].
4. Thymus versus peripheral homeostasis in reconstitution of CD4 T-cell numbers during antiretroviral therapy Early reconstitution does not reflect memory T-cell proliferation. Indeed, the early increase in CD4 T cells involves activated memory CD45RO+ T cells [22–24] that do not incorporate proliferation markers such as Ki67, while the proportions of CD4 T cells positive for Ki67 may even decrease during that early period [29,30,32]. These findings support the hypothesis that sequestered T cells in lymphoid tissues are released in blood circulation when virus replica
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tion is controlled. Nevertheless, infusions in humans of deuterated glucose allowing the in vivo measurement of cell proliferation [40] suggest that some T-cell proliferation could occur during the second phase of CD4 cell reconstitution [22]. During that period a slow increase in numbers of Ki67+ memory T cells is also observed [30]. We have suggested that the interpretation of the Ki67 staining should be cautious. Indeed, less than 1% of these Ki67+ CD4 cells were shown to be in the S or G2-M phases of cell mitosis, while 99% were only in the G1 phase of the cell cycle and corresponded to activated effector T helper cells producing cytokines rather than to proliferating T cells [41]. Naive T cells play a major role in the long-term phase of CD4 reconstitution [25–27,33,34,42]. This increase in naive T cells raised the question of their status toward antigen encounter and their origin. Indeed, some memory T cells can revert to their CD45 isoform from RO to RA. Thus, the naive cell status had to be assessed based on coexpression of CD45RA and CD62L-selectin [25–27,33,42]. An analysis of the repertoire of TCRs used in CD4 T cells also supported the virgin status of these CD4+CD45RA+CD62L+ T cells. The messengers encoding for highly variable regions [CDR3] of the TCRs were shown to rediversify during HAART, as a correlate of naive T-cell increase [43]. In addition, an increase in thymus mass is observed in parallel with respect to naive CD4 T-cell amplification during treatment of HIV-infected adults [41,44]. These observations support the hypothesis that increased thymus output might help replenish the reservoir of naive T cells during HAART. The detection in naive CD4 T cells of the TCR rearrangement excision circles, or TRECs, produced in the thymus during maturation brought definitive evidence that those cells had recently emigrated from the thymus [45]. TRECs do not replicate with the cell genome, providing a good estimate of T-cell turnover in the periphery. The high proportions of TRECs found in CD4+CD45RA+CD62L+ T cells as well as their very low frequencies in memory T cells fit with the phenotypic definition of naive and memory T cells. The TREC proportions decline with age and HIV infection, but increase during HAART. In parallel with naive T-cell recovery during HAART [45–47], an alternative explanation was recently proposed according to which the intense immune activation observed during the course of the disease results in an increased proliferation of naive T cells, thereby decreasing their relative TRECs content [48]. Accordingly, reduction in this abnormal activation with HAART would reduce naive cell proliferation and increase their TREC content, in the context of a constant thymus output. This second hypothesis, however, is in contradiction with the low peripheral turnover of naive T cells as suggested by various models of T-cell homeostasis. Thymus output also depends upon input of bone-marrow progenitors as well as thymocyte proliferation. IL-7 plays a major role in regulating these events. Its production is increased during the natural course of the HIV infection in
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response to T-cell depletion. Inversely, the IL-7 level decreases concurrently with restoration of CD4 counts during HAART. These observations suggest a role of IL-7 in restoration of T-cell homeostasis [49].
5. Control of immune activation contributes to immune reconstitution A rapid and remarkable reduction in the cell surface expression of T-cell activation markers, Fas/Fas-ligand on CD4 T cells occurs in parallel with control of virus replication [25,27,29–31,33,34,50]. Similarly, the levels of plasma inflammatory cytokines TNF-α and IL-6 are also reduced [51]. Both phenomena help to reduce the abnormal rate of cell death observed during the natural course of HIV infection [48] and to restore normal numbers in the T-cell compartments [52]. The same observations were made in primary and chronic HIV infection [33,34]. Altogether, reducing abnormal immune activation in the memory T-cell compartment prolongs their survival and helps to restore their numbers, while facilitating their recirculation and enhancing their functional capacity.
6. Restoration of host defenses: successes and limits CD4 T-cell responses against CMV and mycobacterium tuberculosis in AIDS patients are rapidly restored during antiretroviral therapy [25,27,41,53–55]. This restoration occurs concurrently with memory CD4 cell increase and normalization of the inflammatory syndrome [27,53–57]. In parallel, reconstitution of naive and memory T cells also allows patients to respond to immunization to recall and neo-antigens [58]. In contrast, no restoration of CD4 cell reactivity against HIV itself had been observed in chronically infected patients [25,27,53,54,59,60]. HIV-specific T cells are detected only when HAART is initiated early enough at the time of primary infection [61,62] or before the onset of CD4 depletion [63]. Preservation of virus-specific CD4+ responses is thus dependent on the time of initiation of HAART at the time of primary infection. Notably, there are indications that the CCR5 fusion coreceptor preferentially expressed on the surface of Th1 cells selectively eliminates them. Such dissociation between rapid restoration of strong protective immunity against opportunistic pathogens and crippled immunity against HIV with HAART undoubtedly reflects differences in T-cell exposure to antigenic stimuli. Indeed, residual memory CD4 T cells specific to opportunistic antigens are rapidly restimulated and reexpand since those pathogens are not immediately affected by HAART. In contrast, HAART rapidly reduces HIV antigens impairing appropriate stimulation of HIV-specific CD4 cells that had been severely depleted before treatment. Similarly, a decline in HIV-specific CD8 T cells is reported to parallel virus reduction [64,65]. Despite the fact that some viral
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replication persists during apparently suppressive antiretroviral therapy [66], the HIV antigen load might still be insufficient to allow specific CD4 T-cell expansion [28,67]. Reexposing the immune system to the virus during structured therapeutic interruptions [STI] rapidly amplifies HIV-specific T cells [61]. However, HIV-specific CD4 T cells are expanded only transiently after reexposure to HIV and are rapidly eliminated [64]. A safer strategy for restoring HIV-specific immunity is currently being proposed in patients treated with HAART by reimmunizing against HIV with candidate vaccines rather than with HIV itself [68].
7. Conclusions Three mechanisms allow CD4 recovery: redistribution of memory CD4 T cells from tissues, regeneration of naive T cells from thymus origin and reduction of the inflammatory syndrome. Lack of restoration of solid immunity against HIV itself illustrates the need for antigen stimulation in the homeostasis of antigen-specific T cells.
Acknowledgements We are grateful for the precious collaboration of research groups directed by Professor Christine Katlama and Professor Henry Agut in the Département des maladies infectieuses and the Département de virologie, and Guy Gorochov and Catherine Blanc in the Laboratoire d’immunologie cellulaire, INSERM 543, Hôpital Pitié-Salpétrière, Paris, France.
References
[9]
C. Tanchot, F.A. Lemonnier, B. Perarnau, A.A. Freitas, B. Rocha, Differential requirements for survival and proliferation of CD8 naive or memory T cells, Science 276 (1997) 2057–2062.
[10] T. Brocker, Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells, J. Exp. Med. 186 (1997) 1223–1232. [11]
J. Kiberg, A. Berns, H. von Boehmer, Peripheral T-cell survival requires continual ligation of the T-cell receptor to major histocompatibility complex class II-expressing encoded molecules, J. Exp. Med. 186 (1997) 1269–1275.
[12] A.W. Goldrath, M.J. Bevan, Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts, Immunity 11 (1999) 183–190. [13] H. von Boehmer, P. Kisielow, Lymphocyte lineage commitment: instruction versus selection, Cell 73 (1993) 207–208. [14] Y. Modigliani, G. Coutinho, O. Burlen-Defranoux, A. Coutinho, A. Bandeira, Differential contribution of thymic outputs and peripheral expansion in the development of peripheral T-cell pools, Eur. J. Immunol. 24 (1994) 1223–1227. [15] J. Hassan, D.J. Reen, IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells, Eur. J. Immunol. 28 (1998) 3057–3065. [16] A.T. Vella, M.T. Scherer, L. Schultz, J.W. Kappler, P. Marrack, B cells are not essential for peripheral T-cell tolerance, Proc. Natl. Acad. Sci. USA 93 (1996) 951–955. [17] C.H. June, J.A. Ledbetter, P.S. Linsley, C.B. Thompson, Role of the CD28 receptor in T–cell activation, Immunol. Today 11 (1990) 211–216. [18] M.J. Lenardo, Interleukin-2 programs mouse αß T lymphocytes for apoptosis, Nature 353 (1991) 858–861. [19] O. Janssen, S. Wesselborg, B. Heckl-Ostreicher, K. Pechhold, A. Bender, S. Schondelmaier, G. Moldenhauer, D. Kabelitz, T-cell receptor/CD3-signaling induces death by apoptosis in human T-cell receptor gamma delta + T cells, J. Immunol. 146 (1991) 35–39. [20] F. Hornung, L.X. Zheng, M.J. Lenardo, Maintenance of clonotype specificity in CD95/Apo-1/Fas-mediated apoptosis of mature T lymphocytes, J. Immunol. 159 (1997) 3816–3822. [21] B. Combadiere, C. Reis e Sousa, C. Trageser, L.X. Zheng, C.R. Kim, M.J. Lenardo, Differential TCR signaling regulates apoptosis and immunopathology during antigen responses in vivo, Immunity 9 (1998) 305–313.
[1]
O. Stutman, Intrathymic and extrathymic T-cell maturation, Immunol. Rev. 42 (1978) 138–184.
[2]
B. Rocha, A.A. Freitas, A.A. Coutinho, Population dynamics of T lymphocytes. Renewal rate and expansion in the peripheral lymphoid organs, J. Immunol. 131 (1983) 2158–2164.
[3]
A.A. Freitas, B. Rocha, A.A. Coutinho, Lymphocyte population kinetics in the mouse, Immunol. Rev. 91 (1986) 5–37.
[22] J. Morales, B. Homey, A.P. Vicari, S. Hudak, E. Oldham, J. Hedrick, R. Orozco, N.G. Copeland, N.A. Jenkins, L.M. McEvoy, A. Zlotnik, CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells, Proc. Natl. Acad. Sci. USA 96 (1999) 14470–14475.
[4]
R.A. Miller, O. Stutman, T-cell repopulation from functionally restricted splenic progenitors: 10,000-fold expansion documented by using limiting dilution analyses, J. Immunol. 133 (1984) 2925–2932.
[23] F. Sallusto, D. Lenig, R. Forster, M. Lipp, A. Lanzavecchia, Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature 401 (1999) 708–712.
[5]
B. Rocha, M.P. Lembezat, A. Freitas, A. Bandeira, Interleukin 2 receptor expression and interleukin 2 production in exponentially growing T cells: major differences between in vivo and in vitro proliferating T lymphocytes, Eur. J. Immunol. 19 (1989) 1137–1145.
[24] X. Zhang, S. Sun, I. Hwang, D.F. Tough, J. Sprent, Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15, Immunity 8 (1998) 591–599.
[6]
U. Beutner, H.R. MacDonald, TCR-MHC class II interaction is required for peripheral expansion of CD4 cells in a T cell-deficient host, Int. Immunol. 10 (1998) 305–310.
[7]
B. Ernst, C.D. Surh, J. Sprent, Thymic selection and cell division, J. Exp. Med. 182 (1995) 961–971.
[8]
J. Bender, T. Mitchell, J. Kappler, P. Marrack, CD4+ T-cell division in irradiated mice requires peptides distinct from those responsible for thymic selection, J. Exp. Med. 190 (1999) 367–374.
[25] B. Autran, G. Carcelain, T.S. Li, C. Blanc, D. Mathez, R. Tubiana, C. Katlama, P. Debre, J. Leibowitch, Positive effects of combined antiretroviral therapy on CD4+ T-cell homeostasis and function in advanced HIV disease, Science 277 (1997) 112–116. [26] N.G. Pakker, D.W. Notermans, R.J. de Boer, M.T. Roos, F. de Wolf, A. Hill, J.M. Leonard, S.A. Danner, F. Miedema, P.T. Schellekens, Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation, Nat. Med. 4 (1998) 208–214.
B. Combadière et al. / Microbes and Infection 4 (2002) 575–580 [27] M.M. Lederman, E. Connick, A. Landay, D.R. Kuritzkes, J. Spritzler, M. St Clair, B.L. Kotzin, L. Fox, M.H. Chiozzi, J.M. Leonard, F. Rousseau, M. Wade, J.D. Roe, A. Martinez, H. Kessler, Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315, J. Infect. Dis. 178 (1998) 70–79. [28] W. Cavert, D.W. Notermans, K. Staskus, S.W. Wietgrefe, M. Zupancic, K. Gebhard, K. Henry, Z.Q. Zhang, R. Mills, H. McDade, C.M. Schuwirth, J. Goudsmit, S.A. Danner, A.T. Haase, Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection, Science 276 (1997) 960–964. [29] K. Tenner-Racz, H.J. Stellbrink, J. van Lunzen, C. Schneider, J.P. Jacobs, B. Raschdorff, G. Grosschupff, R.M. Steinman, P. Racz, The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T-cell counts are sites for virus replication and CD4 T-cell proliferation. The impact of highly active antiretroviral therapy, J. Exp. Med. 187 (1998) 949–959. [30] N. Sachsenberg, A.S. Perelson, S. Yerly, G.A. Schockmel, D. Leduc, B. Hirschel, L. Perrin, Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen, J. Exp. Med. 187 (1998) 1295–1303. [31] R.P. Bucy, R.D. Hockett, C.A. Derdeyn, M.S. Saag, K. Squires, M. Sillers, R.T. Mitsuyasu, J.M. Kilby, Initial increase in blood CD4[+] lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues, J. Clin. Invest. 103 (1999) 1391–1398. [32] S. Fleury, G.P. Rizzardi, A. Chapuis, G. Tambussi, C. Knabenhans, E. Simeoni, J.Y. Meuwly, J.M. Corpataux, A. Lazzarin, F. Miedema, G. Pantaleo, Long-term kinetics of T-cell production in HIV-infected subjects treated with highly active antiretroviral therapy, Proc. Natl. Acad. Sci. USA 97 (2000) 5393–5398. [33] G. Carcelain, C. Blanc, J. Leibowitch, P. Mariot, D. Mathez, V. Schneider, A.G. Saimot, F. Damont, F. Simon, P. Debre, B. Autran, P.M. Girard, T-cell changes after combined nucleoside analogue therapy in HIV primary infection, AIDS 13 (1999) 1077–1081. [34] P.G. Rizzardi, G. Tambussi, P.A. Bart, A.G. Chapuis, A. Lazzarin, G. Pantaleo, Virological and immunological responses to HAART in asymptomatic therapy-naive HIV-1-infected subjects according to CD4 cell count, AIDS 14 (2000) 2257–2263. [35] M. Renaud, C. Katlama, A. Mallet, V. Calvez, G. Carcelain, R. Tubiana, M. Jouan, E. Caumes, H. Agut, F. Bricaire, P. Debre, B. Autran, Determinants of paradoxical CD4 cell reconstitution after protease inhibitor containing antiretroviral regiment, AIDS 13 (1999) 669–676. [36] E. Connick, M.M. Lederman, B.L. Kotzin, J. Spritzler, D.R. Kuritzkes, M. St. Clair, L. Fox, M. Heath-Chiozzi, J.M. Leonard, F. Rousseau, J. DArc Roe, A. Martinez, H. Kessler, A. Landay, Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response, J. Infect. Dis. 181 (2000) 358–363. [37] R.T. Schooley, Long term immunologic effects and side effects of successful antiretroviral therapy, Clin. Infect. Dis. 29 (1999) 12–18. [38] K.Y. Smith, H. Valdez, A. Landay, J. Spritzler, B.H. Gross, I.R. Francis, H.A. Kessler, E. Connick, J.M. McCune, M.M. Lederman, Thymic size and Lymphocyte Restoration in HIV infected patients following 48 weeks of therapy with zidovudine, lamivudine and ritonavir, J. Infect. Dis. 181 (2000) 141–147. [39] J.M. McCune, M.B. Hanley, D. Cesar, Factors influencing T-cell turnover in HIV-1 seropositive patients, J. Clin. Invest. 105 (2000) R1–R8. [40] M. Hellerstein, M.B. Hanley, D. Cesar, S. Siler, C. Papageorgopoulos, E. Wieder, D. Schmidt, R. Hoh, R. Neese, D. Macallan, S. Deeks, J.M. McCune, Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans, Nat. Med. 5 (1999) 83–89.
579
[41] B. Combadière, C. Blanc, T. Li, G. Carcelain, C. Delaugerre, V. Calvez, R. Tubiana, P. Debré, C. Katlama, B. Autran, CD4+Ki67+ lymphocytes in HIV-infected patients are effector T cells accumulated in the G1 phase of the cell cycle, Eur. J. Immunol. 30 (2000) 3598–3603. [42] T.S. Li, R. Tubiana, A.M. Fillet, B. Autran, C. Katlama, Negativation of cytomegalovirus blood culture with restoration of CD4+ T-cell reactivity to CMV after HAART in an HIV-1 infected patient, J. Acquired Immune Deficiency Syndromes Human Retrovirol. 20 (1999) 514–515. [43] G. Gorochov, A.U. Neumann, A. Kereveur, C. Parizot, T.S. Li, C. Katlama, M. Karmochkine, G. Raguin, B. Autran, P. Debre, Perturbation of CD4 and CD8 T-cell repertoires during progression to AIDS and influence of antiviral therapy, Nature Med. 4 (1998) 215–221. [44] J.M. McCune, R. Loftus, D.K. Schmidt, P. Carrell, D. Webster, L.B. Swor-Yim, I.R. Francis, B.H. Gross, R.M. Grant, High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection, J. Clin. Invest. 101 (1998) 2301–2308. [45] D.C. Douek, R.D. McFarland, P.H. Keiser, E.A. Gage, J.M. Massey, B.F. Haynes, M.A. Polis, A.T. Haase, M.B. Feinberg, J.L. Sullivan, B.D. Jamieson, J.A. Zack, L.J. Picker, R.A. Koup, Changes in thymic function with age and during the treatment of HIV infection, Nature 396 (1998) 690–695. [46] J.F. Poulin, M.N. Viswanathan, J.M. Harris, K.V. Komanduri, E. Wieder, N. Ringuette, M. Jenkins, J.M. Mc Cune, R.P. Sekaly, Direct evidence for thymic function in adult humans, J. Exp. Med. 190 (1999) 479–486. [47] L. Zhang, S.R. Lewin, M. Markowitz, H.H. Lin, E. Skulsky, R. Karanicolas, Y. He, X. Jin, S. Tuttleton, M. Vesanen, H. Spiegel, R. Kost, J. Lunzen van, H.J. Stellbrink, S. Wolinsky, W. Borkowsky, P. Palumbo, L.G. Kostrikis, D.D. Ho, Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy, J. Exp. Med 190 (1999) 725–732. [48] M.D. Hazenberg, S.A. Otto, J.W. Cohen Stuart, M.C. Verschuren, J.C. Borleffs, C.A. Boucher, R.A. Coutinho, J.M. Lange, T.F. Rinke de Wit, A. Tsegaye, J.J. Dongen van, D. Hamann, R.J. Boer de, F. Miedema, Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T-cell population in HIV-1 infection, Nat. Med. 6 (2000) 1036–1042. [49] L. Napolitano, R.M. Grant, S.G. Deeks, D. Schmidt, S.C. DeRosa, L.A. Herzenberg, B.G. Herndier, J. Andersson, J. Mc Cune, Increased production of IL7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis, Nature Med. 7 (2001) 73–79. [50] J. Andersson, T.E. Fehniger, B.K. Patterson, Early reduction of immune activation in lymphoid tissue following highly active HIV therapy, AIDS 12 (1998) F123–F129. [51] E.M. Sloand, P.N. Kumar, S. Kim, A. Chaudhuri, F.F. Weichold, N.S. Young, Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4[+] T cells and decreases their susceptibility to apoptosis in vitro and in vivo, Blood 94 (1999) 1021–1027. [52] F.F. Weichold, J.L. Bryant, S. Pati, O. Barabitskaya, R.C. Gallo, M.S. Reitz Jr, HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells, J. Hum. Virol. 2 (1999) 261–269. [53] C.R. Rinaldo, J.M. Liebman, X.L. Huang, Z. Fan, A.I. Shboul, D.K. McMahon, Prolonged suppression of human immunodeficiency virus type 1 [HIV-1] viremia in persons with advanced disease results in enhancement of CD4 T-cell reactivity to microbial antigens but not to HIV-1 antigens, J. Infect. Dis. 179 (1999) 329–336.
580
B. Combadière et al. / Microbes and Infection 4 (2002) 575–580
[54] O. Pontesilli, S. Kerkhof-Garde, D.W. Notermans, N.A. Foudraine, M.T. Roos, M.R. Klein, F. Miedema, Functional T-cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy, J. Infect. Dis. 180 (1999) 76–86. [55] T. Wendland, H. Furrer, P.L. Vernazza, HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia, AIDS 13 (1999) 1857–1862. [56] K.V. Komanduri, M.V. Viswanathan, E.D. Wieder, D.K. Schmidt, B.M. Bredt, M.A. Jacobson, J.M. McCune, Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1, Nat. Med. 4 (1998) 953–956. [57] D.V. Havlir, R.D. Schrier, F.J. Torriani, K. Chervenak, J.Y. Hwang, W.H. Boom, Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects, J. Infect. Dis. 182 (2000) 1658–1663. [58] H. Valdez, K.Y. Smith, A. Landay, Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen, AIDS (ACTG 375 team, AIDS Clinical Trials Group) 14 (2000) 11–21. [59] U. Malhotta, M.M. Berrey, Y. Huang, J. Markee, D.J. Brown, S. Ap, L. Musey, T. Schaker, L. Corey, J. Mc Elrath, Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection, J. Infect. Dis. 181 (2000) 121–131. [60] E.S. Rosenberg, J.M. Billingsley, A.M. Caliendo, S.L. Boswell, P.E. Sax, S.A. Kalams, B.D. Walker, Vigorous HIV-1 specific CD4+ T-cell responses associated with control of viremia, Science. 278 (1997) 1447–1452.
[61] A. Oxenius, D.A. Price, P.J. Easterbrook, C.A. O’Callaghan, A.D. Kelleher, J.A. Whelan, G. Sontag, A.K. Sewell, R.E. Phillips, Early highly active antiretroviral therapy for acute HIV-1 infection preserves immunes function of CD8+ and CD4+ T lymphocytes, Proc. Natl. Acad. Sci. USA 97 (2000) 3382–3387. [62] E.S. Rosenberg, M. Altfeld, S.H. Poon, Immune control of HIV-1 after early treatment of acute infection, Nature 407 (2000) 523–526. [63] L. Al-harthi, J. Siegel, J. Spritzler, J. Pottage, M. Agnoli, A. Landay, Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease, AIDS 14 (2000) 761–770. [64] C.M. Gray, J. Lawrence, J.M. Schapiro, J.D. Altman, M.A. Winters, M. Crompton, M. Loi, S.K. Kundu, M.M. Davis, T.C. Merigan, [HAART]Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy, J. Immunol. 162 (1999) 1780–1788. [65] L. Mollet, T.S. Li, A. Samri, C. Tournay, R. Tubiana, Restim and Comet Study Groups, V. Calvez, P. Debré, C. Katlama, B. Autran, Dynamics of HIV-specific CD8+ T lymphocytes with changes in viral load, J. Immunol. 165 (2000) 1692–1704. [66] D. Finzi, J. Blankson, J.D. Siliciano, Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy, Nat. Med. 5 (1999) 512–517. [67] G. Carcelain, R. Tubiana, A. Samri, V. Calvez, C. Delaugerre, H. Agut, C. Katlama, B. Autran, Transient mobilization of human immunodeficiency virus [HIV]-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection, J. Virol. 75 (2001) 234–241. [68] B. Autran, G. Carcelain, Boosting immunity to HIV-can the Virus help? Science 290 (2000) 946–949.
Forum in Immunology
Plasticity of lymphoid compartments during HIV infection and treatments: hopes and limits Béhazine Combadière, Guislaine Carcelain, Patrice Debré, Brigitte Autran * Laboratoire d’immunologie cellulaire et tissulaire, unité INSERM 543, hôpital Pitié-Salpétrière, 83, boulevard de l’Hôpital, 75013 Paris, France
Abstract Immune reconstitution during antiretroviral therapy has recently been shown to depend upon multiple factors at work in T-cell homeostasis, amongst which the reduction of thymus dysfunction and of immune hyperactivation is instrumental. The restoration of host defenses against opportunistic pathogens is, however, balanced by the poor immunity restored against HIV thus giving a satisfying link between antigen stimulation and the reconstitution of immune responses to pathogens. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: HIV; HAART; Homeostasis; TREC
1. Introduction
2. T-lymphocyte homeostasis
HIV infection induces major disorders in T-cell homeostasis that lead to profound CD4 cell depletion and cause severe immunodeficiencies. Antiretroviral drug regimens combining inhibitors of HIV reverse transcriptase and protease, the so-called “highly active antiretroviral therapy” (HAART), opened in 1995 a new era by inducing major CD4 cell increases, the mechanisms of which have been extensively studied since the first reports of immune restoration in 1997. In addition to the recirculation of sequestered memory T cells, reexpansion of naive CD4 T cells and rediversification of the CD4 T-cell repertoires, thymus production and peripheral homeostasis were shown to play central roles. Meanwhile, the host develops a transient and potent primary and memory cytotoxic response against the virus that cannot stop viral replication. These findings illustrate the plasticity of the lymphoid compartment even after the severe alterations induced by the virus. Limits in the restoration of HIV-specific immunity also illustrate the tight equilibrium existing between virus exposure, antigen stimulation and numbers of specific CD4 T cells and CD8 memory responses.
It is commonly accepted that the numbers of T cells in mice and humans are well controlled. AIDS is a typical example of such tight homeostatic control as patient peripheral T-cell count is a key way of monitoring disease progression. The fact that virus infections increase or decrease lymphocyte counts also reflects the rapid and exponential increment in virus-specific T cells, one of the principal host resources for limiting virus and disease progression. AIDS is again a typical example with the major increase in CD8 cell numbers leading to an inversion of the normal CD4/CD8 cell 2:1 ratios even before the CD4 cells are depleted. Once viruses are cleared or controlled the rapid decay in virus antigen production provokes a parallel decrease in virus-specific T-cell numbers to a quasiequilibrium level which might depend on the intensity of the initial burst but also on other poorly understood mechanisms. Such a decrease, however, is rarely observed in HIV infection where the virus is poorly controlled. In normal individuals, naive T cells once created in the thymus move to the periphery where they will encounter antigen. Once they emerge from the thymus, there is plenty of evidence that the peripheral pool of T lymphocytes increases in young animals [1–3]. In adults, the thymus output can be affected under some circumstances: the activity of the thymus can slightly increase in animals with a severe deficiency in the peripheral T-cell pool. The entering of naive T cells into empty peripheral compart
* Corresponding author. Tel.: +33-1-42-17-74-03; fax: +33-1-42-17-7490. E-mail address: [email protected] (B. Autran). © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. PII: S 1 2 8 6 - 4 5 7 9 ( 0 2 ) 0 1 5 7 5 - 7
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ments induces a cell division process that requires interaction with major histocompatibility complex (MHC) proteins as has been seen in animal models [4–9]. In addition, naive T cells do not divide in mature animals with a “full” T-cell compartment. They seem to require exogenous “survival” signals [10,11] such as cytokines IL-7, IL-4 [12,13] and to a lesser extent IL-6 or interactions between TCR and MHC–self peptide complexes [14–17]. Whatever the method of survival required by naive T cells, their major quest remains the encountering of an antigen. During infection by pathogens, the numbers of activated T cells increase rapidly. This phenomenon is driven by appropriate full TCR engagement and use of costimulatory molecules such as CD28, OX-40, LFA-1 [17]. The TCR engagement induces CD4 and CD8 effector functions and IL-2 production that acts as an autocrine division factor. The peripheral pool can then reach a limited number. Different studies have established that T-cell activation predisposes to antigen-induced mature T-cell apoptosis. The original studies by Lenardo [18] and Janssen et al. [19] explicitly demonstrated, in αβ and γδ T cells, respectively, that a key component of antigen-induced apoptosis is IL-2 stimulation and proliferation prior to lethal TCR engagement. This homeostatic phenomenon again tends to reduce the peripheral pool size. The studies by Hornung et al. [20] and Combadière et al. [21] demonstrated that selective TCR signaling regulates lymphocyte fate in an antigen-specific manner, implying that the elaboration of partial signals by the TCR could promote tolerance by benign selection of activated T cells. The latter phenomenon can occur in activated T lymphocytes and participate in nonselective T-cell elimination during the course of the disease. As discussed later, HIV-specific CD4+ T cells seem to be lost in most patients soon after the primary infection and remain detectable only in individuals with low virus production and a low T-cell activation profile. Homeostatic control mechanisms might also have the untoward complication of allowing the immune response to fail when confronted with a rapidly mutating pathogen such as HIV. Another aspect of T-cell alterations during HIV infection is that increasing proportions of T cells bearing activation markers are thus more sensitive to antigen-induced cell death. The very existence and survival of memory T cells has been contested for many years. Exposure to antigens combined with the presence of adjuvant and with the production of inflammatory cytokines might be related to the rapid conversion of antigen-specific naive T cells to antigenspecific memory T cells. What maintains a high frequency of memory T cells is still unknown. It has been recently shown that chemokines may select various types of memory T-cell populations [22,23]. To some extent, survival of memory T cells is controlled by their location. An additional idea is that continuous and slow cell division of memory cells would maintain them under the influence of cytokines such as IL-15 [24]. This cytokine is highly produced by the host during infections. It has been recently shown that
whereas IL-15 increases the number of CD8 cells, IL-2 decreases it. Once again, such a mechanism of memory T-cell survival might fail when confronted with a rapidly mutating virus such as HIV. Thus, with the coexistence of these phenomena, what are the possibilities of ensuring HIV-specific primary and memory immune responses?
3. The kinetics of CD4 cell reconstitution: a two-phase process Antiretroviral treatment rapidly increases CD4 counts, concurrently with the reduction in plasma virus load. This phenomenon has been suggested to reflect a recirculation of T cells from lymphoid tissues [25–27]. Various studies performed on peripheral blood cells and on lymph nodes confirmed this redistribution hypothesis [28–32], which seems to occur at any stage of CD4 cell depletion [33,34]. Such an early rise in the CD4 cell count was shown to be mainly influenced by the intensity of CD4 depletion at initiation of treatment and by the slope of CD4+ T-cell decline during the year prior to treatment initiation [35]. CD4 cell expansion slows down after the third month of treatment but persists over years of successful antiretroviral therapy until the peripheral CD4 counts reach normal or subnormal values [25,26,32,35–37]. This second phase appears to be strongly correlated with the magnitude of the plasma viral load reduction [35,36] but is not related to CD4 depletion at treatment initiation [35] nor to the stage of the disease [35]. These findings suggest that the immune system has the same capacity to repopulate the CD4 compartment whatever the severity of the defects installed before introduction of HAART. The time required to reach normal or subnormal CD4 values can range from 2 to 6 years depending on the disease stage at which treatment had been initiated [32,34–36]. In some patients, however, the CD4 reconstitution appears to be virus-independent. The absence of a CD4 response can contrast with a major and stable viral load reduction in approximately 5% cases [35]. The latter paradoxical CD4 responses might involve various factors such as age, reflecting some impairment in thymus tissue [35–39].
4. Thymus versus peripheral homeostasis in reconstitution of CD4 T-cell numbers during antiretroviral therapy Early reconstitution does not reflect memory T-cell proliferation. Indeed, the early increase in CD4 T cells involves activated memory CD45RO+ T cells [22–24] that do not incorporate proliferation markers such as Ki67, while the proportions of CD4 T cells positive for Ki67 may even decrease during that early period [29,30,32]. These findings support the hypothesis that sequestered T cells in lymphoid tissues are released in blood circulation when virus replica
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tion is controlled. Nevertheless, infusions in humans of deuterated glucose allowing the in vivo measurement of cell proliferation [40] suggest that some T-cell proliferation could occur during the second phase of CD4 cell reconstitution [22]. During that period a slow increase in numbers of Ki67+ memory T cells is also observed [30]. We have suggested that the interpretation of the Ki67 staining should be cautious. Indeed, less than 1% of these Ki67+ CD4 cells were shown to be in the S or G2-M phases of cell mitosis, while 99% were only in the G1 phase of the cell cycle and corresponded to activated effector T helper cells producing cytokines rather than to proliferating T cells [41]. Naive T cells play a major role in the long-term phase of CD4 reconstitution [25–27,33,34,42]. This increase in naive T cells raised the question of their status toward antigen encounter and their origin. Indeed, some memory T cells can revert to their CD45 isoform from RO to RA. Thus, the naive cell status had to be assessed based on coexpression of CD45RA and CD62L-selectin [25–27,33,42]. An analysis of the repertoire of TCRs used in CD4 T cells also supported the virgin status of these CD4+CD45RA+CD62L+ T cells. The messengers encoding for highly variable regions [CDR3] of the TCRs were shown to rediversify during HAART, as a correlate of naive T-cell increase [43]. In addition, an increase in thymus mass is observed in parallel with respect to naive CD4 T-cell amplification during treatment of HIV-infected adults [41,44]. These observations support the hypothesis that increased thymus output might help replenish the reservoir of naive T cells during HAART. The detection in naive CD4 T cells of the TCR rearrangement excision circles, or TRECs, produced in the thymus during maturation brought definitive evidence that those cells had recently emigrated from the thymus [45]. TRECs do not replicate with the cell genome, providing a good estimate of T-cell turnover in the periphery. The high proportions of TRECs found in CD4+CD45RA+CD62L+ T cells as well as their very low frequencies in memory T cells fit with the phenotypic definition of naive and memory T cells. The TREC proportions decline with age and HIV infection, but increase during HAART. In parallel with naive T-cell recovery during HAART [45–47], an alternative explanation was recently proposed according to which the intense immune activation observed during the course of the disease results in an increased proliferation of naive T cells, thereby decreasing their relative TRECs content [48]. Accordingly, reduction in this abnormal activation with HAART would reduce naive cell proliferation and increase their TREC content, in the context of a constant thymus output. This second hypothesis, however, is in contradiction with the low peripheral turnover of naive T cells as suggested by various models of T-cell homeostasis. Thymus output also depends upon input of bone-marrow progenitors as well as thymocyte proliferation. IL-7 plays a major role in regulating these events. Its production is increased during the natural course of the HIV infection in
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response to T-cell depletion. Inversely, the IL-7 level decreases concurrently with restoration of CD4 counts during HAART. These observations suggest a role of IL-7 in restoration of T-cell homeostasis [49].
5. Control of immune activation contributes to immune reconstitution A rapid and remarkable reduction in the cell surface expression of T-cell activation markers, Fas/Fas-ligand on CD4 T cells occurs in parallel with control of virus replication [25,27,29–31,33,34,50]. Similarly, the levels of plasma inflammatory cytokines TNF-α and IL-6 are also reduced [51]. Both phenomena help to reduce the abnormal rate of cell death observed during the natural course of HIV infection [48] and to restore normal numbers in the T-cell compartments [52]. The same observations were made in primary and chronic HIV infection [33,34]. Altogether, reducing abnormal immune activation in the memory T-cell compartment prolongs their survival and helps to restore their numbers, while facilitating their recirculation and enhancing their functional capacity.
6. Restoration of host defenses: successes and limits CD4 T-cell responses against CMV and mycobacterium tuberculosis in AIDS patients are rapidly restored during antiretroviral therapy [25,27,41,53–55]. This restoration occurs concurrently with memory CD4 cell increase and normalization of the inflammatory syndrome [27,53–57]. In parallel, reconstitution of naive and memory T cells also allows patients to respond to immunization to recall and neo-antigens [58]. In contrast, no restoration of CD4 cell reactivity against HIV itself had been observed in chronically infected patients [25,27,53,54,59,60]. HIV-specific T cells are detected only when HAART is initiated early enough at the time of primary infection [61,62] or before the onset of CD4 depletion [63]. Preservation of virus-specific CD4+ responses is thus dependent on the time of initiation of HAART at the time of primary infection. Notably, there are indications that the CCR5 fusion coreceptor preferentially expressed on the surface of Th1 cells selectively eliminates them. Such dissociation between rapid restoration of strong protective immunity against opportunistic pathogens and crippled immunity against HIV with HAART undoubtedly reflects differences in T-cell exposure to antigenic stimuli. Indeed, residual memory CD4 T cells specific to opportunistic antigens are rapidly restimulated and reexpand since those pathogens are not immediately affected by HAART. In contrast, HAART rapidly reduces HIV antigens impairing appropriate stimulation of HIV-specific CD4 cells that had been severely depleted before treatment. Similarly, a decline in HIV-specific CD8 T cells is reported to parallel virus reduction [64,65]. Despite the fact that some viral
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replication persists during apparently suppressive antiretroviral therapy [66], the HIV antigen load might still be insufficient to allow specific CD4 T-cell expansion [28,67]. Reexposing the immune system to the virus during structured therapeutic interruptions [STI] rapidly amplifies HIV-specific T cells [61]. However, HIV-specific CD4 T cells are expanded only transiently after reexposure to HIV and are rapidly eliminated [64]. A safer strategy for restoring HIV-specific immunity is currently being proposed in patients treated with HAART by reimmunizing against HIV with candidate vaccines rather than with HIV itself [68].
7. Conclusions Three mechanisms allow CD4 recovery: redistribution of memory CD4 T cells from tissues, regeneration of naive T cells from thymus origin and reduction of the inflammatory syndrome. Lack of restoration of solid immunity against HIV itself illustrates the need for antigen stimulation in the homeostasis of antigen-specific T cells.
Acknowledgements We are grateful for the precious collaboration of research groups directed by Professor Christine Katlama and Professor Henry Agut in the Département des maladies infectieuses and the Département de virologie, and Guy Gorochov and Catherine Blanc in the Laboratoire d’immunologie cellulaire, INSERM 543, Hôpital Pitié-Salpétrière, Paris, France.
References
[9]
C. Tanchot, F.A. Lemonnier, B. Perarnau, A.A. Freitas, B. Rocha, Differential requirements for survival and proliferation of CD8 naive or memory T cells, Science 276 (1997) 2057–2062.
[10] T. Brocker, Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells, J. Exp. Med. 186 (1997) 1223–1232. [11]
J. Kiberg, A. Berns, H. von Boehmer, Peripheral T-cell survival requires continual ligation of the T-cell receptor to major histocompatibility complex class II-expressing encoded molecules, J. Exp. Med. 186 (1997) 1269–1275.
[12] A.W. Goldrath, M.J. Bevan, Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts, Immunity 11 (1999) 183–190. [13] H. von Boehmer, P. Kisielow, Lymphocyte lineage commitment: instruction versus selection, Cell 73 (1993) 207–208. [14] Y. Modigliani, G. Coutinho, O. Burlen-Defranoux, A. Coutinho, A. Bandeira, Differential contribution of thymic outputs and peripheral expansion in the development of peripheral T-cell pools, Eur. J. Immunol. 24 (1994) 1223–1227. [15] J. Hassan, D.J. Reen, IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells, Eur. J. Immunol. 28 (1998) 3057–3065. [16] A.T. Vella, M.T. Scherer, L. Schultz, J.W. Kappler, P. Marrack, B cells are not essential for peripheral T-cell tolerance, Proc. Natl. Acad. Sci. USA 93 (1996) 951–955. [17] C.H. June, J.A. Ledbetter, P.S. Linsley, C.B. Thompson, Role of the CD28 receptor in T–cell activation, Immunol. Today 11 (1990) 211–216. [18] M.J. Lenardo, Interleukin-2 programs mouse αß T lymphocytes for apoptosis, Nature 353 (1991) 858–861. [19] O. Janssen, S. Wesselborg, B. Heckl-Ostreicher, K. Pechhold, A. Bender, S. Schondelmaier, G. Moldenhauer, D. Kabelitz, T-cell receptor/CD3-signaling induces death by apoptosis in human T-cell receptor gamma delta + T cells, J. Immunol. 146 (1991) 35–39. [20] F. Hornung, L.X. Zheng, M.J. Lenardo, Maintenance of clonotype specificity in CD95/Apo-1/Fas-mediated apoptosis of mature T lymphocytes, J. Immunol. 159 (1997) 3816–3822. [21] B. Combadiere, C. Reis e Sousa, C. Trageser, L.X. Zheng, C.R. Kim, M.J. Lenardo, Differential TCR signaling regulates apoptosis and immunopathology during antigen responses in vivo, Immunity 9 (1998) 305–313.
[1]
O. Stutman, Intrathymic and extrathymic T-cell maturation, Immunol. Rev. 42 (1978) 138–184.
[2]
B. Rocha, A.A. Freitas, A.A. Coutinho, Population dynamics of T lymphocytes. Renewal rate and expansion in the peripheral lymphoid organs, J. Immunol. 131 (1983) 2158–2164.
[3]
A.A. Freitas, B. Rocha, A.A. Coutinho, Lymphocyte population kinetics in the mouse, Immunol. Rev. 91 (1986) 5–37.
[22] J. Morales, B. Homey, A.P. Vicari, S. Hudak, E. Oldham, J. Hedrick, R. Orozco, N.G. Copeland, N.A. Jenkins, L.M. McEvoy, A. Zlotnik, CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells, Proc. Natl. Acad. Sci. USA 96 (1999) 14470–14475.
[4]
R.A. Miller, O. Stutman, T-cell repopulation from functionally restricted splenic progenitors: 10,000-fold expansion documented by using limiting dilution analyses, J. Immunol. 133 (1984) 2925–2932.
[23] F. Sallusto, D. Lenig, R. Forster, M. Lipp, A. Lanzavecchia, Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature 401 (1999) 708–712.
[5]
B. Rocha, M.P. Lembezat, A. Freitas, A. Bandeira, Interleukin 2 receptor expression and interleukin 2 production in exponentially growing T cells: major differences between in vivo and in vitro proliferating T lymphocytes, Eur. J. Immunol. 19 (1989) 1137–1145.
[24] X. Zhang, S. Sun, I. Hwang, D.F. Tough, J. Sprent, Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15, Immunity 8 (1998) 591–599.
[6]
U. Beutner, H.R. MacDonald, TCR-MHC class II interaction is required for peripheral expansion of CD4 cells in a T cell-deficient host, Int. Immunol. 10 (1998) 305–310.
[7]
B. Ernst, C.D. Surh, J. Sprent, Thymic selection and cell division, J. Exp. Med. 182 (1995) 961–971.
[8]
J. Bender, T. Mitchell, J. Kappler, P. Marrack, CD4+ T-cell division in irradiated mice requires peptides distinct from those responsible for thymic selection, J. Exp. Med. 190 (1999) 367–374.
[25] B. Autran, G. Carcelain, T.S. Li, C. Blanc, D. Mathez, R. Tubiana, C. Katlama, P. Debre, J. Leibowitch, Positive effects of combined antiretroviral therapy on CD4+ T-cell homeostasis and function in advanced HIV disease, Science 277 (1997) 112–116. [26] N.G. Pakker, D.W. Notermans, R.J. de Boer, M.T. Roos, F. de Wolf, A. Hill, J.M. Leonard, S.A. Danner, F. Miedema, P.T. Schellekens, Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation, Nat. Med. 4 (1998) 208–214.
B. Combadière et al. / Microbes and Infection 4 (2002) 575–580 [27] M.M. Lederman, E. Connick, A. Landay, D.R. Kuritzkes, J. Spritzler, M. St Clair, B.L. Kotzin, L. Fox, M.H. Chiozzi, J.M. Leonard, F. Rousseau, M. Wade, J.D. Roe, A. Martinez, H. Kessler, Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315, J. Infect. Dis. 178 (1998) 70–79. [28] W. Cavert, D.W. Notermans, K. Staskus, S.W. Wietgrefe, M. Zupancic, K. Gebhard, K. Henry, Z.Q. Zhang, R. Mills, H. McDade, C.M. Schuwirth, J. Goudsmit, S.A. Danner, A.T. Haase, Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection, Science 276 (1997) 960–964. [29] K. Tenner-Racz, H.J. Stellbrink, J. van Lunzen, C. Schneider, J.P. Jacobs, B. Raschdorff, G. Grosschupff, R.M. Steinman, P. Racz, The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T-cell counts are sites for virus replication and CD4 T-cell proliferation. The impact of highly active antiretroviral therapy, J. Exp. Med. 187 (1998) 949–959. [30] N. Sachsenberg, A.S. Perelson, S. Yerly, G.A. Schockmel, D. Leduc, B. Hirschel, L. Perrin, Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen, J. Exp. Med. 187 (1998) 1295–1303. [31] R.P. Bucy, R.D. Hockett, C.A. Derdeyn, M.S. Saag, K. Squires, M. Sillers, R.T. Mitsuyasu, J.M. Kilby, Initial increase in blood CD4[+] lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues, J. Clin. Invest. 103 (1999) 1391–1398. [32] S. Fleury, G.P. Rizzardi, A. Chapuis, G. Tambussi, C. Knabenhans, E. Simeoni, J.Y. Meuwly, J.M. Corpataux, A. Lazzarin, F. Miedema, G. Pantaleo, Long-term kinetics of T-cell production in HIV-infected subjects treated with highly active antiretroviral therapy, Proc. Natl. Acad. Sci. USA 97 (2000) 5393–5398. [33] G. Carcelain, C. Blanc, J. Leibowitch, P. Mariot, D. Mathez, V. Schneider, A.G. Saimot, F. Damont, F. Simon, P. Debre, B. Autran, P.M. Girard, T-cell changes after combined nucleoside analogue therapy in HIV primary infection, AIDS 13 (1999) 1077–1081. [34] P.G. Rizzardi, G. Tambussi, P.A. Bart, A.G. Chapuis, A. Lazzarin, G. Pantaleo, Virological and immunological responses to HAART in asymptomatic therapy-naive HIV-1-infected subjects according to CD4 cell count, AIDS 14 (2000) 2257–2263. [35] M. Renaud, C. Katlama, A. Mallet, V. Calvez, G. Carcelain, R. Tubiana, M. Jouan, E. Caumes, H. Agut, F. Bricaire, P. Debre, B. Autran, Determinants of paradoxical CD4 cell reconstitution after protease inhibitor containing antiretroviral regiment, AIDS 13 (1999) 669–676. [36] E. Connick, M.M. Lederman, B.L. Kotzin, J. Spritzler, D.R. Kuritzkes, M. St. Clair, L. Fox, M. Heath-Chiozzi, J.M. Leonard, F. Rousseau, J. DArc Roe, A. Martinez, H. Kessler, A. Landay, Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response, J. Infect. Dis. 181 (2000) 358–363. [37] R.T. Schooley, Long term immunologic effects and side effects of successful antiretroviral therapy, Clin. Infect. Dis. 29 (1999) 12–18. [38] K.Y. Smith, H. Valdez, A. Landay, J. Spritzler, B.H. Gross, I.R. Francis, H.A. Kessler, E. Connick, J.M. McCune, M.M. Lederman, Thymic size and Lymphocyte Restoration in HIV infected patients following 48 weeks of therapy with zidovudine, lamivudine and ritonavir, J. Infect. Dis. 181 (2000) 141–147. [39] J.M. McCune, M.B. Hanley, D. Cesar, Factors influencing T-cell turnover in HIV-1 seropositive patients, J. Clin. Invest. 105 (2000) R1–R8. [40] M. Hellerstein, M.B. Hanley, D. Cesar, S. Siler, C. Papageorgopoulos, E. Wieder, D. Schmidt, R. Hoh, R. Neese, D. Macallan, S. Deeks, J.M. McCune, Directly measured kinetics of circulating T lymphocytes in normal and HIV-1 infected humans, Nat. Med. 5 (1999) 83–89.
579
[41] B. Combadière, C. Blanc, T. Li, G. Carcelain, C. Delaugerre, V. Calvez, R. Tubiana, P. Debré, C. Katlama, B. Autran, CD4+Ki67+ lymphocytes in HIV-infected patients are effector T cells accumulated in the G1 phase of the cell cycle, Eur. J. Immunol. 30 (2000) 3598–3603. [42] T.S. Li, R. Tubiana, A.M. Fillet, B. Autran, C. Katlama, Negativation of cytomegalovirus blood culture with restoration of CD4+ T-cell reactivity to CMV after HAART in an HIV-1 infected patient, J. Acquired Immune Deficiency Syndromes Human Retrovirol. 20 (1999) 514–515. [43] G. Gorochov, A.U. Neumann, A. Kereveur, C. Parizot, T.S. Li, C. Katlama, M. Karmochkine, G. Raguin, B. Autran, P. Debre, Perturbation of CD4 and CD8 T-cell repertoires during progression to AIDS and influence of antiviral therapy, Nature Med. 4 (1998) 215–221. [44] J.M. McCune, R. Loftus, D.K. Schmidt, P. Carrell, D. Webster, L.B. Swor-Yim, I.R. Francis, B.H. Gross, R.M. Grant, High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection, J. Clin. Invest. 101 (1998) 2301–2308. [45] D.C. Douek, R.D. McFarland, P.H. Keiser, E.A. Gage, J.M. Massey, B.F. Haynes, M.A. Polis, A.T. Haase, M.B. Feinberg, J.L. Sullivan, B.D. Jamieson, J.A. Zack, L.J. Picker, R.A. Koup, Changes in thymic function with age and during the treatment of HIV infection, Nature 396 (1998) 690–695. [46] J.F. Poulin, M.N. Viswanathan, J.M. Harris, K.V. Komanduri, E. Wieder, N. Ringuette, M. Jenkins, J.M. Mc Cune, R.P. Sekaly, Direct evidence for thymic function in adult humans, J. Exp. Med. 190 (1999) 479–486. [47] L. Zhang, S.R. Lewin, M. Markowitz, H.H. Lin, E. Skulsky, R. Karanicolas, Y. He, X. Jin, S. Tuttleton, M. Vesanen, H. Spiegel, R. Kost, J. Lunzen van, H.J. Stellbrink, S. Wolinsky, W. Borkowsky, P. Palumbo, L.G. Kostrikis, D.D. Ho, Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy, J. Exp. Med 190 (1999) 725–732. [48] M.D. Hazenberg, S.A. Otto, J.W. Cohen Stuart, M.C. Verschuren, J.C. Borleffs, C.A. Boucher, R.A. Coutinho, J.M. Lange, T.F. Rinke de Wit, A. Tsegaye, J.J. Dongen van, D. Hamann, R.J. Boer de, F. Miedema, Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T-cell population in HIV-1 infection, Nat. Med. 6 (2000) 1036–1042. [49] L. Napolitano, R.M. Grant, S.G. Deeks, D. Schmidt, S.C. DeRosa, L.A. Herzenberg, B.G. Herndier, J. Andersson, J. Mc Cune, Increased production of IL7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis, Nature Med. 7 (2001) 73–79. [50] J. Andersson, T.E. Fehniger, B.K. Patterson, Early reduction of immune activation in lymphoid tissue following highly active HIV therapy, AIDS 12 (1998) F123–F129. [51] E.M. Sloand, P.N. Kumar, S. Kim, A. Chaudhuri, F.F. Weichold, N.S. Young, Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4[+] T cells and decreases their susceptibility to apoptosis in vitro and in vivo, Blood 94 (1999) 1021–1027. [52] F.F. Weichold, J.L. Bryant, S. Pati, O. Barabitskaya, R.C. Gallo, M.S. Reitz Jr, HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells, J. Hum. Virol. 2 (1999) 261–269. [53] C.R. Rinaldo, J.M. Liebman, X.L. Huang, Z. Fan, A.I. Shboul, D.K. McMahon, Prolonged suppression of human immunodeficiency virus type 1 [HIV-1] viremia in persons with advanced disease results in enhancement of CD4 T-cell reactivity to microbial antigens but not to HIV-1 antigens, J. Infect. Dis. 179 (1999) 329–336.
580
B. Combadière et al. / Microbes and Infection 4 (2002) 575–580
[54] O. Pontesilli, S. Kerkhof-Garde, D.W. Notermans, N.A. Foudraine, M.T. Roos, M.R. Klein, F. Miedema, Functional T-cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy, J. Infect. Dis. 180 (1999) 76–86. [55] T. Wendland, H. Furrer, P.L. Vernazza, HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia, AIDS 13 (1999) 1857–1862. [56] K.V. Komanduri, M.V. Viswanathan, E.D. Wieder, D.K. Schmidt, B.M. Bredt, M.A. Jacobson, J.M. McCune, Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1, Nat. Med. 4 (1998) 953–956. [57] D.V. Havlir, R.D. Schrier, F.J. Torriani, K. Chervenak, J.Y. Hwang, W.H. Boom, Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects, J. Infect. Dis. 182 (2000) 1658–1663. [58] H. Valdez, K.Y. Smith, A. Landay, Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen, AIDS (ACTG 375 team, AIDS Clinical Trials Group) 14 (2000) 11–21. [59] U. Malhotta, M.M. Berrey, Y. Huang, J. Markee, D.J. Brown, S. Ap, L. Musey, T. Schaker, L. Corey, J. Mc Elrath, Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection, J. Infect. Dis. 181 (2000) 121–131. [60] E.S. Rosenberg, J.M. Billingsley, A.M. Caliendo, S.L. Boswell, P.E. Sax, S.A. Kalams, B.D. Walker, Vigorous HIV-1 specific CD4+ T-cell responses associated with control of viremia, Science. 278 (1997) 1447–1452.
[61] A. Oxenius, D.A. Price, P.J. Easterbrook, C.A. O’Callaghan, A.D. Kelleher, J.A. Whelan, G. Sontag, A.K. Sewell, R.E. Phillips, Early highly active antiretroviral therapy for acute HIV-1 infection preserves immunes function of CD8+ and CD4+ T lymphocytes, Proc. Natl. Acad. Sci. USA 97 (2000) 3382–3387. [62] E.S. Rosenberg, M. Altfeld, S.H. Poon, Immune control of HIV-1 after early treatment of acute infection, Nature 407 (2000) 523–526. [63] L. Al-harthi, J. Siegel, J. Spritzler, J. Pottage, M. Agnoli, A. Landay, Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease, AIDS 14 (2000) 761–770. [64] C.M. Gray, J. Lawrence, J.M. Schapiro, J.D. Altman, M.A. Winters, M. Crompton, M. Loi, S.K. Kundu, M.M. Davis, T.C. Merigan, [HAART]Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy, J. Immunol. 162 (1999) 1780–1788. [65] L. Mollet, T.S. Li, A. Samri, C. Tournay, R. Tubiana, Restim and Comet Study Groups, V. Calvez, P. Debré, C. Katlama, B. Autran, Dynamics of HIV-specific CD8+ T lymphocytes with changes in viral load, J. Immunol. 165 (2000) 1692–1704. [66] D. Finzi, J. Blankson, J.D. Siliciano, Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy, Nat. Med. 5 (1999) 512–517. [67] G. Carcelain, R. Tubiana, A. Samri, V. Calvez, C. Delaugerre, H. Agut, C. Katlama, B. Autran, Transient mobilization of human immunodeficiency virus [HIV]-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection, J. Virol. 75 (2001) 234–241. [68] B. Autran, G. Carcelain, Boosting immunity to HIV-can the Virus help? Science 290 (2000) 946–949.