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Immune activation and AIDS pathogenesis

Sodora, Donald La; Silvestri, Guidob,c

doi: 10.1097/QAD.0b013e3282f2dbe7
Editorial Review

From the aDepartment of Medicine, University of Texas Southwestern, Dallas, Texas, USA

bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

cYerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.

Received 31 May, 2007

Revised 24 September, 2007

Accepted 2 October, 2007

Correspondence to G. Silvestri, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 705 Stellar-Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104, USA. Tel: +215 573 5363; fax: +215 573 5369; e-mail:

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The mechanisms by which HIV induces the immune dysfunction clinically defined as AIDS have been a subject of intense study since the discovery of the virus in the early 1980s. Initial virological analysis demonstrated low levels of virus replication in infected patients, suggesting that the virus alone was incapable of inducing AIDS and that additional factors must also play a role in determining the HIV-associated immunologic dysfunction. This concept has recently been emphasized from a statistical perspective by the observation that while the level of HIV replication is significantly correlated with the risk of disease progression [1], this parameter only predicts a minor part of the variation in the rate of progression among infected patients [2]. In the mid 1990s, improvements in the techniques available to detect HIV demonstrated that virus replication was active throughout the course of the disease [3,4]. In addition, the observation that inhibition of viral replication with antiretroviral drugs substantially attenuates disease progression established very clearly that virus replication is responsible for pathogenicity. What remains poorly defined, however, is the mechanistic linkage between virus replication and the onset of AIDS.

A model of CD4 T-cell depletion based entirely on direct virus infection and killing of these cells was put forward in the mid 1990s [5,6]. This so-called ‘tap-and-drain’ model proposed that progression to AIDS in HIV-infected individuals resulted from a failure of the immune system's homeostatic response to keep up with a high rate of loss of CD4 T cells [5,6]. The model offered an explanation for the rapid increase of CD4 T-cell counts following inhibition of virus replication by antiretroviral therapy. However, this model and its later versions [7,8] were challenged on theoretical and experimental grounds as they did not appear to grasp the complexity of T-cell dynamics in response to ongoing viral replication and painted a simplistic picture of AIDS pathogenesis [9–17].

The idea that chronic immune activation plays a major role in AIDS pathogenesis was first put forward by Ascher and Sheppard [18] and, in parallel – but from a rather different perspective – by Grossman and colleagues in the late 1980s/early 1990s [19,20]. Shortly thereafter, Giorgi and colleagues published a series of clinical studies supporting the concept that an excessive/aberrant immune activation is a fundamental driving force for the HIV-associated immune dysfunction. These studies identified the level of CD8 T-cell activation, as determined by CD38 and HLA-DR expression, as a better correlate of disease progression than viral load [21–24]. While exact characterization of the HIV-associated chronic immune activation remains incomplete, an activation/dysfunction phenotype is apparent for many different immune cell types in HIV infection. With regard to T-cells, the assessment of immune activation can be made through: (i) high frequency of T cells expressing markers of activation and proliferation [25–27]; (ii) high levels of activation-induced apoptosis of uninfected T cells [28–32]; (iii) high levels of T-cell proliferation as measured by direct labeling [15,33,34]. A higher proliferation rate in HIV-infected subjects compared to uninfected individuals is not restricted to CD4 and CD8 T cells, but also observed in B cells, natural killer (NK) cells and macrophages [7,15,33]. Strong indirect support for the crucial role of immune activation in AIDS pathogenesis is provided by studies of SIV infections of natural hosts, in which high levels of virus replication are not sufficient to induce progression to AIDS in the absence of increased levels of immune activation [35–40].

This body of experimental evidence implicating a central role for immune activation in AIDS pathogenesis represents the backdrop for this article. Here we discuss the key questions that are central to this important issue in contemporary HIV/AIDS research.

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To what extent (if any) does immune activation reflect homeostatic pressure on the T-cell compartment?

There is wide consensus that during pathogenic HIV/SIV infection the level of T-cell proliferation and turnover is significantly increased when compared to that of healthy individuals. Conceptually, an increased T-cell turnover could reflect homeostatic proliferation in response to the cell losses induced by the virus or, alternatively, immune responses to antigenic stimulation and/or pro-inflammatory signals. These mechanisms are not mutually exclusive and in fact may be interrelated [41], but it should be kept in mind that while the above-mentioned ‘tap-and-drain’ model postulated an almost perfect quantitative balance between the rate of infected cell death on the one hand, and the rate of a compensatory/homeostatic CD4 T-cell proliferation on the other, several observations suggested a much more complex and indirect mechanistic and causal relations between CD4 T-cell killing by virus, immune activation, and T-cell turnover. First, CD8 T-cells, which are not directly targeted by the virus, also show increased rates of activation and proliferation [7,15,33]. Second, suppression of virus replication by antiretroviral therapy (ART) is followed by a rapid decline of proliferating CD4 T-cells at a time when the absolute number of these cells is still low [27]. Finally, the majority of CD4 T-cell death involves uninfected cells [42]. The currently prevailing view is that these cells die as a consequence of their previous activation, that their death is not directly responsible for the slow depletion of CD4 T-cells and that other consequences of chronic immune activation drive the pathogenic process leading to AIDS [9–17]. Grossman and colleagues also proposed that the heightened turnover of T cells during chronic HIV infection largely consists of overlapping bursts of proliferation and differentiation in response to T-cell receptor mediated stimuli and inflammation [13,17,43,44]. Direct support for the hypothesis that T-cell turnover is antigen driven has been provided by studies performed in SIVmac239-infected rhesus macaques using extensive in vivo labeling of dividing cells with BrdU and tracing the kinetics of labeled T cells in blood and in lymphoid and nonlymphoid tissues [45,46].

Homeostatic pressure on the T-cell regenerative compartment likely occurs during pathogenic HIV/SIV infection, mainly as a consequence of the progressive depletion of naive and central memory T cells that are known to be subject to strict homeostatic regulation. Depletion of these cells, in turn, appears to be caused in large part by the chronic immune activation rather than the direct cytopathic effect of the virus. Furthermore, homeostatic proliferation (i.e., occurring in response to depletion) and classical immune activation-related proliferation (i.e., antigen-specific T-cell responses) are not necessarily distinct phenomena, but, rather, may overlap significantly. For instance, a scenario could be envisioned where a pro-inflammatory environment favors the activation of certain T-cell clones that may then become particularly prone to respond to homeostatic stimuli such as interleukin (IL)-7, IL-15 and others. Of note, linking ‘homeostatic proliferation’ to ‘immune activation’ in this way, within the framework of an immune activation oriented approach to the pathogenesis of HIV/SIV disease progression, bears no resemblance to a pathogenic model of HIV/SIV infection whereby CD4 T-cells are progressively depleted simply because their ‘homeostatic’ replication in response to viral killing collapses over time.

Another interesting question is how tissue-specific CD4 T-cell homeostasis (particularly in the mucosa associated lymphoid tissue, MALT) is maintained under normal circumstances and, in the context of HIV/SIV, whether and to what extent an increased homing of activated/memory CD4 T-cells in the MALT may compensate for the early loss of mucosal CD4CCR5 T cells. This point is important as the loss of mucosal CD4 T effector-memory (TEM) cells appears to be a critical determinant of progression to AIDS during both early and chronic phases of SIV infection of Indian rhesus macacques [45,46]. However, it is still unclear whether, in this model, the failure of reconstituting the mucosal CD4 TEM pool is primarily related to events occurring at the level of MALT (due to excessive virus-mediated cell destruction) as opposed to an upstream collapse of the CD4 central memory T (TCM) cell pool from which these CD4 TEM cells originate. A recent analysis of the dynamics of the input of CD4 T cells from the pool of lymph node-based TCM cells to that of MALT-based TEM cells during SIV infection supported the second view, although a defect in recruiting and/or retaining long-lived CD4 TEM cells in MALT due to the indirect effect of viral replication has also been implicated [46].

A better understanding of how CD4 T-cell homeostasis is regulated in the face of immune activation and how this regulation affects the physiologic events of CD4 T-cell activation, proliferation, and migration to effector tissues will help us elucidate the mechanisms of AIDS pathogenesis and hopefully pave the way to novel therapeutic approaches aimed directly at replenishing the CD4 T-cell pool in HIV-infected individuals.

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To what extent is immune activation a cause versus a consequence of the immune damage?

There is a broad consensus among investigators that, during pathogenic HIV/SIV infections, disease progression is closely associated with the level of immune activation. As discussed above, the majority of available data suggest that immune activation is most likely a cause of the damage to the immune system rather than being simply its consequence. Interestingly, immunologic studies in mice indicated that chronic immune activation may result in severe immune dysfunction and opportunistic infections even in absence of virus infection [47].

Naturally, immune activation that reflects specific responses to opportunistic infections (OI) can be considered a consequence of the immune dysfunction that was caused by the virus. These OI-specific immune responses, however, are a secondary and relatively late cause of immune activation, which is clearly established long before opportunistic infections occur. More complex is the relationship between immune activation and microbial translocation from a damaged intestinal lumen into systemic circulation. Recent work by Douek and his colleagues [48,49] suggests that the HIV/SIV-induced depletion of mucosal CD4 T cells results in the loss of mucosal integrity and thereby could trigger, or contribute to, the abnormal levels of chronic immune activation. It should be noted, however, that microbial translocation does not occur in SIV-infected sooty mangabeys (SM) and African green monkeys (AGM) despite a depletion of mucosal CD4 T cells that is comparable to that observed in pathogenic infections [49,52]. These latter observations indicate that factors other than the local depletion of CD4 T cells per se cause or contribute to the loss of mucosal integrity and microbial translocation associated with pathogenic HIV/SIV infection. Such additional factors might be related to the early establishment of pro-inflammatory tissue environments in human patients, but not in SM, or the depletion of non-CD4 T cells such as macrophages or dendritic cells during pathogenic infection. In any event, even assuming that all or most of the HIV-associated immune activation is caused by microbial translocation due to the loss of MALT CD4 T cells occurring during the first few weeks of infection, chronic immune activation remains the key to the ongoing systemic deletion of CD4 T cells, which is the best correlate to date of disease progression in humans.

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What causes immune activation in HIV infection?

While there is a broad consensus among investigators that immune activation plays an important role in AIDS pathogenesis, much debate remains as to what causes the HIV-associated immune activation. Many in the field now accept the idea that this phenomenon is multifactorial in nature. We have compiled a list of potential factors that are most likely to contribute to the chronic, generalized immune activation observed during pathogenic HIV or SIV infection (Table 1). The first is the direct effect of HIV on T cells. HIV might directly influence immune activation through binding of the envelope protein gp120/160 to CD4 and/or CCR5, resulting in intracellular signaling [53–55]; or through the ability (or lack thereof) of HIVnef to down-modulate the expression of CD3-T cell receptor (TCR) in the infected cells [56]. The second factor capable of inducing systemic immune activation is the host immune response to HIV/SIV. This activation is likely to be initiated at the level of innate immunity – particularly involving plasmacytoid dendritic cells through Toll-like receptor (TLR) stimulation [57,58] – resulting in the activation of adaptive HIV-specific immune responses (humoral and cellular). The role of the virus-specific adaptive immune response (and, most notably, the HIV-specific cytotoxic T-cell response) is particularly complex due to its dual nature, i.e., beneficial as it may suppress virus replication, but harmful as it fuels chronic T-cell activation once the virus has escaped the immune response. Third, it was recently proposed that the HIV-associated immune activation is caused in part by translocation of microbial products from the intestinal lumen to the systemic circulation, where they can activate the immune system by binding to certain TLR (i.e., TLR-2, 4, 5, 6) [48,49]. This model postulates that microbial translocation (of which plasma levels of lipopolysaccahride is a reliable marker) occurs as a result of the depletion of intestinal lamina propria CD4 T cells and monocyte/macrophages through to direct cytopathic effect of the virus. It is also important to note that other pathogens, including but not limited to those causing OI during the later stages of disease, might also be playing roles in the HIV-associated immune activation [59–61]. For example, helminth infections may result in a more rapid progression to AIDS, possibly by augmenting the level of activation of the immune system [60]. A fourth potential factor is the non-antigen specific bystander activation of T and B lymphocytes caused by increased production of pro-inflammatory cytokines (e.g., tumor necrosis factor-α, IL-1, and others). This production, in turn, is also induced at the level of innate immune response to the HIV/SIV replication and is mediated by various types of accessory cells that are chronically activated. While the mechanisms of this ‘bystander’ activation are still relatively obscure, it is possible that they also involve the up-regulation of apoptosis related molecules (CD95, TRAIL, DR4/5) on the surface of T cells, thus making them prone to activation-induced cell death [28–32,54,62]. The last potential factor is the depletion and/or dysfunction of CD4 regulatory T cells (Treg) that normally suppress immune activation via mechanisms involving direct cell-to-cell contact, production of cytokines, and inhibition of dendritic cell activity. The role of Treg in HIV and SIV infection has been the subject of intense study over the past few years [63–76]. Conceivably, Treg may play a dual role in HIV/SIV infection, i.e., protective if suppressing the chronic immune activation but harmful if attenuating effective T-cell responses. This dual role of Treg, together with the fact that these cells appear to work in a tissue-specific manner, makes it difficult to interpret correlations between their number and functional state in blood samples and HIV disease progression.

Table 1

Table 1

Two still unanswered questions are: (i) why HIV infected individuals fail to effectively control the level of immune activation, as do natural host species infected with SIV, and (ii) why does the excessive activation not resolve as it does in other chronic viral infections (e.g., hepatitis C virus, hepatitis B virus). While the comparison with these may not be altogether appropriate as these viruses do not preferentially infect immune system cells, the case of non-pathogenic SIV infection of African monkey species is particular intriguing as these infections are strikingly similar to pathogenic HIV/SIV infections in terms of the level of virus replication, target cell tropism, and ineffectiveness of antiviral immune responses [50,51,77].

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Why is the HIV-induced immune activation so disruptive to the immune system?

In considering this issue, it should be noted from the outset that although many lines of evidence indicate that chronic immune activation is a key determinant of immunodeficiency in HIV-infected individuals, the exact mechanisms by which this phenomenon induces CD4 T-cell depletion and disease progression are still largely unknown, and in fact may vary in different classes of patients. The possibilities discussed below are largely hypothetical.

Since HIV is known to replicate more efficiently in activated CD4 T lymphocytes [78], chronic immune activation is probably instrumental in sustaining viral replication by providing available targets for HIV replication. In this context, the preferential activation, infection and killing of HIV-specific CD4 T cells [79] is probably detrimental as it results in the loss of CD4 T-cell help, potentially contributing to the exhaustion/failure of CD8-mediated cytotoxic T lymphocytes responses to the virus. Another consequence of HIV-associated chronic immune activation that may have negative consequences in the long term is the expansion of activated ‘effector’ T (TE) cells of both CD4 and CD8 lineages [9,13,16]. The expansion of a pool of fast-replicating but short-lived CD4 TE cells may indirectly facilitate CD4 T-cell depletion. First, the expansion of CD4 TE cells may come at the expense of the naive and memory T-cell pools. A continuous drain from these pools could, in turn, result in a reduced capacity of the immune system to generate primary and anamnestic responses to antigens. Chronic immune activation may also result in the proliferative senescence of the T-cell pool, particularly at the level of CD4 TCM cells [46], thus supporting the interesting concept of AIDS as a disease characterized by a prematurely ageing immune system [80]. Second, expansion of activated TE cells may be accompanied by the production of pro-inflammatory and pro-apoptotic cytokines that complete the vicious cycle sustaining the generalized immune activation associated with pathogenic HIV/SIV infections. Third, the chronic pro-inflammatory environment has also multiple suppressive effects at different levels. It interferes with the function of several immune cell types, such as B cells, NK, γ δ T-cells, dendritic cells, and monocytes [81–86], and may impair the regenerative capacity of the immune system at the levels of bone marrow, thymus, and lymph nodes [87–90]. Interestingly, the increase in CD4 T cell counts that follows ART appears to be better correlated, at least in certain situations, with the favorable effect of ART on reducing immune activation and apoptosis rather than with its direct suppressive effect on HIV replication [91–94].

In summary, the hypothetical mechanisms by which T-cell immune activation causes disease progression in HIV-infected individuals can be grouped in three main classes: (i) stimulation of naive and memory CD4 T-cell activation, proliferation and differentiation, leading to increased CCR5 expression that renders these cells more susceptible to infection; (ii) alterations of long-term homeostasis of the naive and memory T-cell pools that lead to their gradual depletion and that interfere with the capacity of the host to effectively mount adaptive immune responses; (iii) induction of inflammation and fibrosis, likely destroying secondary lymphoid tissue niches required for the production and homeostasis of CD4 T cells.

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What experiments should be done to further test the immune activation hypothesis?

There is ample consensus among investigators that further experimentation – particularly in vivo studies conducted in the simian model of infection – is needed to ascertain and better characterize the pathogenic role of immune activation during HIV infection. Ideally, the best type of ‘experiment’ would involve treatment of SIV-infected macaques with drugs that either reduce or, alternatively, heighten the level of immune activation in vivo and then assess their effects on immune function and disease progression. Such experimental strategy should include treatment of SIV-infected macaques with TLR antagonists, chloroquine, or antibiotics. An additional interesting approach would be to determine whether artificially increasing the level of immune activation in natural SIV hosts such as SM and AGM (in which low immune activation is typically associated with a non-pathogenic infection) would result in signs of immunodeficiency. In this view, an interesting possibility is testing the ‘bacterial translocation’ hypothesis in SM and/or AGM by the administration of one or more bacterial TLR ligands to these animals during SIV infection. For studies aimed at modulating (i.e., increasing or decreasing) the HIV/SIV associated immune activation, the type, dose, and route of administration of the intervention agents, as well as the timing (acute versus chronic infection) are all important factors that require careful consideration in the design of these future experiments. More generally, it will be important to conduct studies aimed at determining which of the available models of pathogenic SIV infection in macaques (i.e., which virus, which species, etc.) demonstrates a degree of immune activation and disease progression that best resembles HIV infection in humans. Recent interesting comparative studies of Indian and Chinese rhesus macaques indicate that Indian rhesus tend to progress more rapidly to overt disease compared to Chinese rhesus [95]. The pattern of immune activation observed in Chinese macaques (particularly as assessed by the relative expansion of CD4CCR5 T cells) also suggests that infection of these animals may be more representative of HIV infection [96].

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Should we treat immune activation in HIV-infected patients? If so, when and how?

As mentioned above, a large set of data suggest that targeting the HIV-associated immune activation may represent a promising therapeutic strategy to be considered, in addition to ART, in the clinical management of HIV infection. However, the fact that the pathophysiologic mechanisms underlying this chronic activation are still poorly understood is a major obstacle to the implementation of a safe and effective immunosuppressive approach, especially when considering that, ultimately, HIV infection results in a state of immunodeficiency and that the wrong kind of immunosuppression might exacerbate this condition. The interventions should be carefully targeted, mechanism based and hypothesis driven, as preliminary studies have demonstrated that broad-spectrum immunosuppressive agents (such as cyclosporine and mycophenolate) are unlikely to provide the specificity that will enable the immune system to downregulate its hyperactivation and recover [97–101]. Novel and better ‘targeted’ immune interventions should be tested in short-term, proof-of-concept clinical trials conducted in small groups of well characterized patients treated during chronic infection (perhaps those defined, immunologically, as non-responders to ART or showing discordant response). As noted earlier, the line between ‘immune modulation’ and ‘immune reconstitution’ is not as clear-cut as was previously thought, and it is possible that the beneficial immunological effect of cytokines such as IL-2 and IL-7 may not only, or not primarily, lie in the improvement of CD4 T-cell homeostasis but also in reducing the prevailing level of T-cell activation and apoptosis. Finally, it is interesting to observe that ongoing clinical trials of CCR5 blockade in patients with dual-tropic viruses may allow us to assess whether blocking CCR5 signaling can reduce immune activation and improve the overall immune function, beyond the intended purpose of blocking virus entry and replication. In any immuno-modulatory intervention to be used in HIV-infected individuals, an important issue is how to best monitor changes in the existing level and pattern of immune activation. Unfortunately, none of the available cellular markers of T-cell activation or proliferation (HLA-DR, CD38, Ki67, loss of CD127, and others) seems to be able to consistently and robustly assess the level of the HIV-associated immune activation across all subsets of HIV-infected patients. It will be important to design studies in which multiple potential markers of immune activation are measured longitudinally in a sufficiently large cohort of HIV-infected individuals and the relative value of each of these markers, or of particular combinations, in predicting disease progression is assessed.

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The Authors also wish to thank B. Autran, S. Deeks, D. Douek, M. Feinberg, Z. Grossman, M. Lederman, F. Miedema, and L. Picker for the helpful discussion, and J. Milush, M. Paiardini, and A. Chahroudi for critical reading of this manuscript.

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