Premature ageing of the immune system: the cause of AIDS?

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Premature ageing of the immune system: the cause of AIDS? Victor Appay and Sarah L. Rowland-Jones The reasons for the failure of the immune system to control HIV-1 infection, and the resulting immunodeficiency, remain unclear. HIV-1 persists in its host despite vigorous immune responses, including a strong, and probably functional, HIV-specific cytotoxic T-lymphocyte response. Interestingly the immunological features of HIV-1-infected individuals show many similarities to those seen in elderly people without HIV infection. We propose that, through a process of continuous immune activation, HIV-1 infection leads to an acceleration of the adaptive immune system ageing process, resulting in premature exhaustion of immune resources, which participates in the onset of immunodeficiency. This hypothesis might shed new light on HIV-1 pathogenesis and could suggest the need to reconsider current immunotherapeutic strategies to fight the virus. Published online: 24 October 2002

Victor Appay* Sarah L. Rowland-Jones MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK OX3 9DS. *e-mail: vappay@ gwmail.jr2.ox.ac.uk

Despite the expenditure of considerable energy and resources over two decades, fundamental questions about HIV-1 pathogenesis remain unresolved, and we still lack effective preventative and therapeutic means to eradicate the virus. Progress is hindered by our failure to elucidate the precise causes of the clinical immunodeficiency that almost inevitably develops during chronic HIV-1 infection. Nor is it clear why the immune system appears initially to succeed but ultimately fails to control viral replication. Although viral escape with specific mutations in the epitopes recognized by cytotoxic T lymphocytes (CTLs) can correlate with rapid clinical decline (reviewed in [1]), this might not explain all cases of disease progression. CTLs have a crucial role in the control of infection with many viruses. The eventual failure to contain HIV-1 might arise because of a functional impairment of HIV-specific CTLs (reviewed in [2]), however, this is not necessarily the case. To add to the confusion, emerging evidence suggests that high levels of immune activation, which one might think would be helpful to fight the virus, are actually associated with poor outcome in HIV-1 infection [3]. Our aim is to highlight recent data that might help to clarify the role of CD8+ T-cells in the control of HIV-1, as well as to suggest new insights into the ultimate failure of the immune system to control HIV-1 infection, leading to the development of AIDS. HIV-specific CD8+ T-cell response: impaired or fully functional?

Primary HIV-1 infection is characterized by rapid expansions of HIV-specific ‘effector’ CD8+ T cells, http://immunology.trends.com

resulting in substantial reduction of viraemia. The dynamics of this response are similar to those observed in mouse models of other virus infections, which suggests that the primary CD8+ T-cell response to HIV-1 is not abnormal [4]. However, the virus is never cleared, and significant viraemia can often be detected in patients during chronic infection. It is intriguing that HIV-specific CD8+ T cells at this stage of infection have features of an intermediate stage of cellular differentiation, with low levels of perforin and persistent CD27 expression [5]. This observation generated the hypothesis that HIV-specific CTLs are immature and unable to differentiate fully [6]. However, there is no evidence that this intermediate stage of differentiation is associated with significant functional impairment. It is equally feasible that CTLs of this intermediate phenotype might represent the normal immune response to HIV-1 [7]. CD27+CD28−perforinlow CTLs are found in the great majority of HIV-infected patients, even those with good viral control in the absence of antiviral therapy [so-called long-term non-progressors (LTNPs)] or those with successful viral suppression on therapy [5], both situations when HIV-specific CD4+ T-cell help might be preserved. In other infections, such as Epstein-Barr virus (EBV), hepatitis C virus (HCV) and influenza, where the viruses are adequately controlled, CTLs can be found at an even earlier stage of differentiation, also with low levels of perforin [5,8]. It is plausible that each virus elicits, or even dictates, a CTL response with distinct characteristics and differentiation state. This might be related to the level of activation induced by the virus, with greater activation driving further differentiation; the size of virus specific CD8+ T-cell populations, which might reflect the previous levels of activation, appears to correlate with its state of differentiation (V. Appay et al., unpublished). The HIV-specific CTL response might, therefore, be the appropriate one for this infection. Ex vivo studies of HIV-specific CD8+ T cells, which are mainly found in a resting state during chronic infection, suggest that these cells are in fact fully functional, with the majority able to produce antiviral cytokines and chemokines on stimulation [9,10] and exhibiting specific cytotoxic potential [5,11], although this might be relatively low compared to the more differentiated perforinhigh cytomegalovirus (CMV)-specific T-cell cytotoxicity [9]. Following viral rebound, new and/or pre-existing HIV-specific CD8+ T cells can be activated and expand, showing clear signs of responsiveness to high levels of virus replication [12]. Furthermore, the rapid selection of variants that escape the dominant CTL response in acute simian immunodeficiency virus (SIV) infection [13], together with the complete loss of viral control during both acute and chronic SIV infection in monkeys depleted of CD8+ T cells [14,15], argue strongly in favor of functional CTLs, at least in the SIV model.

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Box 1. HIV-1 strategies to evade host immunity • Of major importance is the unique ability of HIV-1 to mutate under selection pressure, enabling the rapid emergence of variants that can elude both humoral [a] and T-cell recognition from the earliest stages of infection [b,c]. A recent study performed at a population level emphasizes the full extent by which the virus population is shaped by T-cell recognition [d]. • The establishment of latent reservoirs, through the non-productive infection of long lived cell [e], confers on the virus the capacity to remain hidden from immune surveillance and to pursue low levels of replication throughout the lifetime of the infected person [f]. • HIV-1 infection results in a selective depletion of the CD4+ T-cell population, and in particular HIV-specific CD4+ T cells [g]. These cells represent an essential element of the immune response, and their depletion probably impedes virus elimination [h]. • Furthermore, the generation of new immune responses to viral variants might be impaired as a result of the infection of the thymus [i] and professional antigen-presenting cells [j]. • Finally, additional virulence effects, such as the downregulation of MHC class I molecules from the surface of infected cells, might further impede recognition by cytotoxic T lymphocytes [k]. References a Poignard, P. et al. (1999) Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438

b Borrow, P. et al. (1997) Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3, 205–211 c O’Connor, D.H. et al. (2002) Acute phase cytotoxic T-lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat. Med. 8, 493–499 d Moore, C.B. et al. (2002) Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439–1443 e Chun, T.W. et al. (1997) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 f Finzi, D. et al. (1999) 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, 512–517 g Douek, D.C. et al. (2002) HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 h Kalams, S.A. and Walker, B.D. (1998) The critical need for CD4 help in maintaining effective cytotoxic T-lymphocyte responses. J. Exp. Med. 188, 2199–2204 i Brooks, D.G. et al. (2001) Generation of HIV latency during thymopoiesis. Nat. Med. 7, 459–464 j Rowland-Jones, S.L. (1999) HIV: the deadly passenger in dendritic cells. Curr. Biol. 9, R248–R250 k Collins, K.L. et al. (1998) HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401

The functional competence of HIV-specific CD8+ T cells could eventually fail during the late stages of infection, when studies have shown impaired cytokine production [16] and reduced CD3ζ expression [17] by these cells. However, this coincides with the general collapse of the immune system during the development of AIDS. Thus, overall, HIV-specific CD8+ T cells appear in a functional state throughout most of the course of infection. Why then is the virus not eradicated, even in patients with the clearest signs of virus control, such as LTNPs? Why, in the face of continuing viral replication, do Table 1 Changes in the adaptive immune system in HIV-1 infection and human ageing Immune characteristics

HIV-1 infection

Human ageing

Inverted CD4:CD8 ratio + CD4 T-lymphopenia Decreased thymic output Reduced naïve-cell numbers a Changes in cytokine profile (IL-2 reduction, IFN-γ no change or increase) ex vivo Reduced capacity to proliferate to mitogens in vitro + Shorter telomere length in the CD8 T-cell population Increased susceptibility to activationinduced cell death in vitro Accumulation of late differentiated cells + + CD8 and CD4 HIV protein effects on immune function (e.g. HLA class I downregulation by nef) Increased susceptibility to common infections Increased susceptibility to opportunistic infections

[50] [18] [19] [18] [24]

[51] ±E [19] [52] [52]

[21]

[53]

[20]

[54]

[25]

[52]

[26,55]

[29]

[56]

±E

[50]

[52]

[50]

±E

a

Abbreviations: HLA, human leukocyte antigen; IFN, interferon; IL, interleukin. Characteristic not associated with human ageing.

b

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HIV-specific CTLs remain mostly in the resting state? HIV-1 has developed numerous strategies to evade host immunity (Box 1), which clearly diminish the ability of the host to fight the virus. The combination of CD4+ T-cell depletion and immune escape could be particularly significant, generating a situation in which the action threshold for HIV specific CTLs is effectively raised, so that an optimal CTL response is not triggered by low levels of viral replication around the viral setpoint. Thus, even if their function is not directly impaired, HIV-specific CTLs might be unable to mount an effective response to eradicate the virus. Parallels between HIV-1 pathogenesis and human ageing

Regardless of the success or otherwise of immune control, HIV-1 infection almost invariably leads ultimately to rising viral loads and the onset of immunodeficiency. HIV is unique in that it induces CD4+ T-cell depletion, considered to be the best marker of disease progression to date. However, HIV-1-infected individuals also show several dramatic immunological alterations (Table 1), some or all of which probably also contribute to the development of AIDS. Although there has been considerable debate about the dynamics of T-cell turnover in HIV-1 infection, the broad consensus is that the lifespan of both CD4+ and CD8+ T cells is shortened to around a third of normal and, although there is a modest increase in CD8+ T-cell output, the production of naïve CD4+ T cells does not keep pace with CD4+ T-cell destruction [18], probably as a result of thymic dysfunction in HIV-1 infection [19]. Telomere length is significantly shortened in the CD8+ lymphocyte population of HIV-1-infected patients [20], which might relate to a decreased proliferative capacity [21]. Accumulation of

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Box 2. Post-thymic development of CD8+ and CD4+ T cells According to the expression of cell surface markers, both CD4+ and CD8+ T-cell populations can be divided into distinct subpopulations, which exhibit different functional characteristics and homing capacities [a–c]. This has led to a putative model of T-cell differentiation or post-thymic development [d,e], along which sequential downregulations or upregulations of cell-surface molecules (including costimulatory receptors, adhesion molecules but also chemokine receptors [f] and NK-like receptors [g]) occur. The model shown (Fig. I) presents distinct differentiation subsets of CD8+ and CD4+ T cells (described in a resting state), together with characteristic patterns of surface molecules and expression of soluble factors, as well as functional features. Chronic activation probably has an important role in further driving T-cell differentiation, although other factors, many still unclear, could be involved. As T cells differentiate further, they tend to lose some proliferative

capacity, associated with a shortening of telomere lengths (which can be used as an indication of the extent of cell division) owing to reduced telomerase activity (still controversial for CD4+ T cells), so that late differentiated cells (CD28−/CD27−) are considered, in some studies, as end-stage senescent cells [h], displaying a restricted, oligoclonal T-cell repertoire. Accordingly the T-cell differentiation pathway might be related to a process of T-cell senescence, although more studies, particularly carried out in vivo, are needed to confirm this. Of interest is the apparent similarity between both CD4+ and CD8+ T-cell subsets in their patterns of differentiation. Late differentiated CD8+ T cells show increased cytotoxic potential, although CD4+ T cells at this stage acquire cytotoxicity for the first time; the reasons behind this gain in cytotoxic potential remain to be understood, and the role of these cells in conferring protective immunity in vivo is open to debate.

CD8+

CD4+

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Naïve cells CD28+ CD27+ CD11alow CCR7+ CD45RA+

Antigen experienced cells 'Early' High proliferative capacity Help to B-cell differentiation CD28+ CD27+ CD11ahigh CCR7–/+ CD45RA–/+

CD28+ CD27+ CD11alow CCR7+ CD45RA+

Differentiation

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IFN-γ+ IL-2+ Perforin+ Granzyme A+

'Late'

Antigen experienced cells 'Early' High proliferative capacity Help to B-cell differentiation CD28+ CD27+ CD11ahigh CCR7–/+ CD45RA–/+

IFN-γ+ IL-2+ Perforin– Granzyme A–

'Late' Cytotoxic potential Restricted T-cell repertoire Short telomere length?

High cytotoxic potential Restricted T-cell repertoire Short telomere length CD28– CD27– CD11ahigh CCR7– CD45RA+/–

IFN-γ++ IL-2– Perforin++ Granzyme A+

CD28– CD27– CD11ahigh CCR7– CD45RA–/+

IFN-γ++ IL-2– Perforin++ Granzyme A+

Accumulation in HIV-infected individuals TRENDS in Immunology

Fig. I. Distinct differentiation subsets of CD8+ and CD4+ T cells. Abbreviations: IFN, interferon; IL, interleukin.

References a De Rosa, S.C. et al. (2001) 11-color, 13-parameter flow cytometry: identification of human naïve T cells by phenotype, function, and T-cell receptor diversity. Nat. Med. 7, 245–248 b Hamann, D. et al. (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 c Hintzen, R.Q. et al. (1993) Regulation of CD27 expression on subsets of mature T-lymphocytes. J. Immunol. 151, 2426–2435 d Hamann, D. et al. (1999) Faces and phases of human CD8 T-cell development. Immunol. Today 20, 177–180 e Appay, V. et al. (2002) Characterization of CD4(+) CTLs ex vivo. J. Immunol. 168, 5954–5958

oligoclonal antigen-experienced populations with restricted T-cell receptor (TCR) usage is associated with CMV and HIV-1 infection [22,23]; a narrowing of the T-cell repertoire probably reduces the ability to respond to emerging HIV-1 variants, as well as to http://immunology.trends.com

f Wills, M.R. et al. (2002) Identification of naïve or antigen-experienced human CD8(+) T cells by expression of costimulation and chemokine receptors: analysis of the human cytomegalovirus-specific CD8(+) T-cell response. J. Immunol. 168, 5455–5464 g Tarazona, R. et al. (2000) Increased expression of NK-cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech. Ageing Dev. 121, 77–88 h Effros, R.B. and Pawelec, G. (1997) Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion? Immunol. Today 18, 450–454

common and opportunistic pathogens. All of these changes, together with alterations in cytokine secretion [decreased interleukin-2 (IL-2) production and increased interferon-γ (IFN-γ) production] [24] and increased susceptibility to activation-induced

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cell death [25] (as observed in vitro in response to mitogenic stimulation), might reflect the shift in the T-cell population towards increasingly differentiated antigen experienced cells (Box 2). Elevated proportions of terminally differentiated cells (CD28−/CD27−), in both CD4+ and CD8+ T-cell compartments, have been observed in HIV-1-infected individuals. Similar findings have also been associated with several other inflammatory disorders (e.g. CMV and EBV infections, rheumatoid arthritis, ankylosing spondylitis) [5,26–28]. With normal ageing, increased proportions of CD28−CD8+ T cells show a correlation with falling numbers of CD4+ T cells [29]. Moreover, a recent study reported that the fraction of perforin-expressing HIV-specific CD8+ T cells (presumably late differentiated) correlates with disease progression [30]. Taken together, these observations suggest that increased proportions of late differentiated cells might develop in adverse conditions. This process of T-cell differentiation or post-thymic development has also been referred to as the ‘ageing of the T-lymphocyte population’ [31]. A comparison of the immunological changes observed in HIV-1-infected individuals, with those accumulated with age in the HIV-1-uninfected elderly, shows interesting similarities (Table 1), which might help our understanding of the progression of HIV infection. During ageing a reduction in T-cell renewal together with a progressive enrichment of terminally differentiated T cells, thought to be consequence of immune activation over time, translate into a general decline of the immune system, gradually leading to immunosenescence. Both HIV-1 infection and human ageing result, ultimately, in clinical immunodeficiency, characterized by an increased susceptibility to common infectious diseases. It has to be stressed that, although resembling immune senescence in some aspects, AIDS presents a much more severe immunodeficiency. Some immune defects in HIV-1 infection resemble those normally seen in the elderly but there are others that are more specific (such as CD4+ T-lymphopenia), which might underly the significantly increased susceptibility to opportunistic pathogens observed during clinical AIDS (Table 1). Exhaustion of immune resources by HIV-1 leads to AIDS

Some of the damage directly related to HIV replication (e.g. CD4+ T-cell depletion) can be limited through therapeutic viral suppression. However, those defects that are common to both HIV infection and ageing, presumably resulting from successive rounds of T-cell activation, could be irreversible and affect the entire immune system. In HIV-1 infection, huge demands are placed on the immune resources of the infected person. During primary infection there is massive immune activation, in part to generate an HIV-1 specific response capable of reducing plasma viraemia that peaks at millions of particles per milliliter of blood. Thereafter, viral load settles at a stable level, or http://immunology.trends.com

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‘setpoint’, which probably represents a fragile equilibrium between continuing viral replication with the generation of new HIV-1 variants, and immune control with the development of adaptive responses [32]. Although viral load might become undetectable during chronic infection, persistent low level replication, together with detectable viral rebounds, assure the maintenance of chronic immune activation, resulting in the induction of vigorous HIV-specific immune responses (which in extreme cases might account for 22% of CD8+ T cells [33]). Importantly, HIV-1 infection might also result in indirect immune activation, through the depletion of antigen-specific CD4+ T cells, which lowers the threshold for common and/or opportunistic infections to develop. These pathogens can further drive the expansion of activated cells, and, therefore, participate in general immune-system activation (V. Appay, unpublished). For instance, CMV infection, common in HIV-1-infected individuals, might have a significant role in the ageing process of lymphocyte populations. Large numbers of CMV-specific CD8+ T cells in late stages of T-cell differentiation are found in HIV-1infected CMV seropositive donors [5], who generally experience more rapid disease progression than CMV seronegative subjects [34]. Interestingly, CMV infection in the elderly has also been associated with alterations in T-cell subsets [35] and an increase in morbidity [36]. Increased immune activation and constant T-cell turnover could, therefore, generate premature ageing of the immune system and exhaustion of immune resources. As this occurs, the fragile balance between functional HIV-specific CD8+ T-cell activity and ongoing HIV-1 replication is broken. Uncontrolled viral replication rapidly depletes the CD4+ T cell and antigen-presenting cell (APC) populations, leading to immune collapse. The more rapid progression towards AIDS associated with higher viral setpoints might relate to more extensive immune activation and resulting immune exhaustion. The pace of this process might vary depending on the intrinsic pathogenicity of the virus, host genetic factors and also environmental factors. For instance, less pathogenic viruses (such as those with attenuating nef mutations) are more readily controlled and are associated with clinical non-progression [37]. HIV-2, which leads to long term non-progression in the majority of infected people, is associated with low levels of immune activation [3]. Similarly, individuals who generate effective HIV-specific responses in primary infection, perhaps targeting epitopes for which escape mutants are deleterious for the virus, control the virus well from the start and establish a lower viral setpoint [38]. The more rapid disease progression reported in Kenyan prostitutes has been linked to frequent intercurrent infection and related immune activation [39]. Also, accelerated SIV-induced disease progression was reported in SIV infected macaques, which were subjected to repeated SIV-independent immune stimulus to mimic chronic activation [40]. Moreover

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(a)

(b) HIV infection

Human ageing

3 – 25 years

50 – 100 years

Viral setpoint CTL action threshold

HIV load 'Ideal' virus load

Susceptible to common infections and opportunistic infections

CTL 'activated' 'resting' Immune resources TRENDS in Immunology

Fig. 1. Schematic representation of the hypothetical course of HIV-1 infection compared to human ageing. (a) During primary HIV-1 infection, HIV-specific CD8+ cytotoxic T lymphocytes (CTLs) are quickly generated, achieving a significant drop in viral load but fail to eradicate the virus, as a result of HIV immune-escape strategies. Subsequently, HIV-specific CD8+ CTLs respond to viral blips or rebounds around the viral setpoint during chronic infection. However, through the driving of persistent immune activation, general immune resources are progressively depleted so that HIV-specific CD8+ CTLs lose total control of the virus, resulting ultimately in the onset of clinical immunodeficiency. (b) Throughout the lifespan of an HIV-1 uninfected person, the normal maintenance of immune responsiveness to a variety of challenges gradually depletes immune resources. An imaginary infection with an ‘ideal’ virus (influenza-like), which does not directly damage the immune system and is cleared by CTL responses, is depicted.

HIV-infected individuals classified as high responders to HIV, CMV and herpes simplex virus (HSV) antigens were, surprisingly, reported to be at higher risk of more rapid disease progression [41]. However, this could also be explained by enhanced HIV or SIV replication within activated CD4+ T cells and macrophages, thus, hastening the course of disease progression. It has also been speculated that increased levels of immune activation are responsible for increased susceptibility to HIV-1 infection and disease in developing countries [42]. Lastly, it was reported that the age at HIV-1 infection is associated with significantly more rapid disease progression [43], although this remains controversial [44], it could reflect the impact of HIV-1 on an already ageing immune system. Concluding remarks: implications for strategies to fight HIV-1

Acknowledgements We gratefully acknowledge Peter Beverley and Paul Moss for helpful comments and discussion.

We hypothesize that HIV-1 infection, through a continuous process of both direct and indirect immune activation, might accelerate the ageing or decay of the adaptive immune system; so that a 25-year-old person with HIV-1 might exhibit some of the immune characteristics displayed by an uninfected person four times his age (Fig. 1). This hypothesis is consistent with models proposed in previous reports [45,46]. Multiparameter studies to compare the immune characteristics of HIV-infected http://immunology.trends.com

individuals and the HIV-uninfected elderly, in relation to their clinical status, might reveal common markers of the onset of immunodeficiency. In addition, studies of host immune competence in animal models of persistent immune stimulation, independent of SIV or HIV infection, would also provide valuable information to test this hypothesis. As clinical research progresses, there is increasing interest in immune-based therapies in the fight against HIV infection (reviewed in [47]). However, in the light of our proposed hypothesis, the development of such strategies requires great caution and should take into consideration the potential effects of these interventions on the immune system as a whole. Continuous anti-retroviral therapy suppresses viral replication and, thereby, slows down the course of disease progression, by preventing CD4+ T-cell depletion [48] but possibly also by reducing the level of immune responses related to the virus. However, interrupted therapy, including structured treatment interruptions (STI) that enable viral rebounds, could promote immune activation and potentially cause faster disease progression. Similarly, attempts at immune reconstitution using IL-2 or IL-15 could be double-edged swords. Although these stimulatory cytokines might, on the one hand, expand CD4+ T-cell numbers and HIV-specific T-cell responses in HIV-1-infected individuals, on the other hand, they might also contribute to disease pathology by driving T-cell activation and differentiation, leading more rapidly to immunosenescence. Even the effect of vaccines aimed at stimulating HIV-specific T-cell responses in infected individuals should be viewed with caution; is an expansion of antigen-experienced cells advantageous in this context, especially considering that the virus might have already mutated to escape recognition? Moreover, should we favor the expansion of perforinhigh late-differentiated cells [8], when these cells could have characteristics of replicative senescence? Alternatively, strategies aimed at reducing chronic immune activation might prove effective in

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delaying the onset of immunodeficiency and/or minimizing ageing of the T-lymphocyte population. For instance, the use of partially immunosuppressive drugs References 1 Klenerman, P. et al. (2002) HIV: current opinion in escapology. Curr. Opin. Microbiol. 5, 408 2 Lieberman, J. et al. (2001) Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98, 1667–1677 3 Sousa, A.E. et al. (2002) CD4 T-cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J. Immunol. 169, 3400–3406 4 Appay, V. et al. (2002) Dynamics of T-cell responses in HIV infection. J. Immunol. 168, 3660–3666 5 Appay, V. et al. (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379–385 6 Champagne, P. et al. (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 7 Gamadia, L.E. et al. (2002) Skewed maturation of virus-specific CTLs? Nat. Immunol. 3, 203 8 Speiser, D.E. et al. (2002) In vivo activation of melanoma-specific CD8(+) T cells by endogenous tumor antigen and peptide vaccines. A comparison to virus-specific T cells. Eur. J. Immunol. 32, 731–741 9 Appay, V. et al. (2000) HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 10 Goulder, P.J. et al. (2000) Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children. J. Exp. Med. 192, 1819–1832 11 Mueller, Y.M. et al. (2001) Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T Cells. Immunity 15, 871–882 12 Mollet, L. et al. (2000) Dynamics of HIV-specific CD8+ T lymphocytes with changes in viral load. The RESTIM and COMET Study Groups. J. Immunol. 165, 1692–1704 13 Allen, T.M. et al. (2000) Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390 14 Schmitz, J.E. et al. (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–886 15 Jin, X. et al. (1999) Dramatic rise in plasma viremia after CD8(+) T-cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 16 Kostense, S. et al. (2002) Persistent numbers of tetramer+CD8+ T cells but loss of interferon-γ+ HIV-specific T cells during progression to AIDS. Blood 99, 2505–2511 17 Trimble, L.A. and Lieberman, J. (1998) Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 ζ, the signaling chain of the T-cell receptor complex. Blood 91, 585–594 18 Hellerstein, M. et al. (1999) Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat. Med. 5, 83–89 19 Douek, D.C. et al. (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695

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or attempts at modulating telomere lengths to prevent replicative senescence [49] could represent interesting novel approaches to HIV-1 therapy.

20 Wolthers, K.C. et al. (1996) T-cell telomere length in HIV-1 infection: no evidence for increased CD4+ T-cell turnover. Science 274, 1543–1547 21 Clerici, M. et al. (1989) Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J. Clin. Invest. 84, 1892–1899 22 Wang, E.C. et al. (1995) CD8highCD57+ T lymphocytes in normal, healthy individuals are oligoclonal and respond to human cytomegalovirus. J. Immunol. 155, 5046–5056 23 Wilson, J.D. et al. (1998) Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific. J. Exp. Med. 188, 785–790 24 Fan, J. et al. (1993) Elevated IFN-γ and decreased IL-2 gene expression are associated with HIV infection. J. Immunol. 151, 5031–5040 25 Gougeon, M.L. and Montagnier, L. (1993) Apoptosis in AIDS. Science 260, 1269–1270 26 Appay, V. et al. (2002) Characterization of CD4(+) CTLs ex vivo. J. Immunol. 168, 5954–5958 27 Namekawa, T. et al. (1998) Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 41, 2108–2116 28 Schirmer, M. et al. (2002) Circulating cytotoxic CD8(+) CD28(−) T cells in ankylosing spondylitis. Arthritis Res. 4, 71–76 29 Nociari, M.M. et al. (1999) Postthymic development of CD28−CD8+ T-cell subset: age-associated expansion and shift from memory to naïve phenotype. J. Immunol. 162, 3327–3335 30 Heintel, T. et al. (2002) The fraction of perforinexpressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection. AIDS 16, 1497–1501 31 Globerson, A. and Effros, R.B. (2000) Ageing of lymphocytes and lymphocytes in the aged. Immunol. Today 21, 515–521 32 Douek, D.C. et al. (2002) A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T-cell responses reveals a potential mechanism for control of viral escape. J. Immunol. 168, 3099–3104 33 Papagno, L. et al. Comparison between HIV and CMV specific T-cell responses in long term HIV infected donors. Clin. Exp. Immunol. (in press) 34 Webster, A. et al. (1992) Cytomegalovirus (CMV) infection, CD4+ lymphocyte counts and the development of AIDS in HIV-1-infected haemophiliac patients. Clin. Exp. Immunol. 88, 6–9 35 Khan, N. et al. (2002) Cytomegalovirus seropositivity drives the CD8 T-cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169, 1984–1992 36 Wikby, A. et al. (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. Exp. Gerontol. 37, 445–453 37 Dyer, W.B. et al. (1999) Strong human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1. J. Virol. 73, 436–443 38 Migueles, S.A. et al. (2000) HLA B*5701 is highly associated with restriction of virus replication in a

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subgroup of HIV-infected long term nonprogressors. Proc. Natl. Acad. Sci. U. S. A. 97, 2709–2714 Anzala, A.O. et al. (2000) Acute sexually transmitted infections increase human immunodeficiency virus type 1 plasma viremia, increase plasma type 2 cytokines and decrease CD4 cell counts. J. Infect. Dis. 182, 459–466 Villinger, F. et al. (2001) Chronic immune stimulation accelerates SIV-induced disease progression. J. Med. Primatol. 30, 254–259 Schrier, R.D. et al. (1996) Pathogenic and protective correlates of T-cell proliferation in AIDS. HNRC Group. HIV Neurobehavioral Research Center. J. Clin. Invest. 98, 731–740 Grossman, Z. et al. (2002) CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat. Med. 8, 319–323 Darby, S.C. et al. (1996) Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. UK Haemophilia Centre Directors’ Organisation. Lancet 347, 1573–1579 Keller, M.J. et al. (1999) Is age a negative prognostic indicator in HIV infection or AIDS? Aging (Milano) 11, 35–38 Effros, R.B. (2000) Telomeres and HIV disease. Microbes Infect. 2, 69–76 Bestilny, L.J. et al. (2000) Accelerated replicative senescence of the peripheral immune system induced by HIV infection. AIDS 14, 771–780 Allen, T.M. et al. (2002) STI and beyond: the prospects of boosting anti-HIV immune responses. Trends Immunol. 23, 456–460 Carcelain, G. et al. (2001) Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following anti-retroviral therapy. Curr. Opin. Immunol. 13, 483–488 Hodes, R.J. et al. (2002) Opinion: telomeres in T and B cells. Nat. Rev. Immunol. 2, 699–706 Gottlieb, M.S. et al. (1981) Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N. Engl. J. Med. 305, 1425–1431 Wikby, A. et al. (1998) Changes in CD8 and CD4 lymphocyte subsets, T-cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech. Ageing Dev. 102, 187–198 Pawelec, G. et al. (1999) T cells and aging (update February 1999). Front. Biosci. 4, D216–269 Franceschi, C. et al. (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18, 1717–1720 Rufer, N. et al. (1999) Telomere fluorescence measurements in granulocytes and T-lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 Wolthers, K.C. et al. (1996) Increased expression of CD80, CD86 and CD70 on T cells from HIV-infected individuals upon activation in vitro: regulation by CD4+ T cells. Eur. J. Immunol. 26, 1700–1706 Schwartz, O. et al. (1996) Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat. Med. 2, 338–342