The role of the thymus in HIV infection: a 10 year perspective

Fang, Raphael Ho Tsonga,†; Colantonio, Arnaud Da; Uittenbogaart, Christel Ha,b,c,d

doi: 10.1097/QAD.0b013e3282f2589b
Editorial Review
Author Information

From the aDepartments of Microbiology, Immunology, and Molecular Genetics, USA

bPediatrics, USA

cUCLA AIDS Institute, USA

dJonsson Comprehensive Cancer Center, David E. Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Current address: Hôpital Necker-Enfants malades, Unité développement normal et pathologique du système immunitaire, INSERM U-768, 149, rue de Sèvres, 75015 Paris, France.

Received 14 September, 2007

Accepted 18 September, 2007

Correspondence to Christel H. Uittenbogaart, Dept. of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1747, USA. E-mail:

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Despite substantial progress over the last 10 years the exact role of the thymus in HIV-1 infection and HIV-1 pathogenesis is still under investigation. Much has been learned of the types of cells in the thymus that are targets for CXCR4 and CCR5 HIV-1 isolates. In addition, it has become clear that even the adult thymus continues to function, although at a much lower level in uninfected patients, and is able to export naive T cells to the periphery. Changes in thymus function can be evaluated by several methods, including determination of naive T-cell subsets using multicolor flow cytometry and T-cell receptor excision circles (TREC), as well as thymus size and metabolic labeling assays [1–5]. Although each of these measures has its advantages and drawbacks [6], combinations of these parameters provide a picture of the contribution of thymic output and homeostatic proliferative expansion (HPE) to peripheral blood T-cell homeostasis. The importance of the thymus in regenerating a functional immune system has been clearly shown after chemotherapy, bone marrow transplantation and highly active retroviral therapy (HAART) in HIV infection [5,7–10]. The data published during the last 10 years also show that a possible increase in thymic output has an instrumental role in the immunopathogenesis that takes place during the clinically asymptomatic phase of HIV-1 infection.

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Development of the thymic environment and hematopoietic progenitors in the human thymus

The thymus is an encapsulated organ with thymic stroma and hematopoietic cells and consists of several lobules containing distinct cortical and medullary areas [11] (Fig. 1). Cortical and medullary thymic epithelial cells (TEC) are of endodermal origin and constitute the main components of the thymic microenvironment [12]. Although a common progenitor for cortical and medullary TEC was recently identified, each TEC subset plays a distinct role in development of thymocytes [12,13]. Studies by Haynes et al. showed that the human thymus develops early during gestation with T-cell precursors entering the thymic rudiment as early as 7–8 weeks of gestation [14]. There is evidence that crosstalk between thymic stroma and developing thymocytes is essential for a functional thymus [15,16]. Therefore, genetic or pathogenic changes in either thymic stroma or developing T cells have negative consequences for normal T-cell development and the immune system in general.

The earliest progenitors entering the thymus are CD34+ hematopoietic stem cells derived from fetal liver and bone marrow with the capacity to develop into multiple lineages including lymphoid, myeloid and erythroid [17]. In addition to development of CD34+ cells in the thymus into TCR α/β cells, they have the ability to differentiate into TCR γ/δ, NK–T cells, plasmacytoid DC (pDC), myeloid derived or conventional DC (cDC), B and natural killer cells as well as myeloid lineage cells (Fig. 2). Development of non-T cells is not, however, dependent on the thymic microenvironment (reviewed in [18]) [19].

Although there are reports suggesting that progenitor commitment to the T-cell lineage in the bone marrow can occur before CD34+ cells enter the thymus [20], others do not support this concept [21] (reviewed in [18]). CD34+CD7+ lymphoid progenitors able to develop in vitro into the T/NK lineage, or B and NK cells, but lacking myeloid differentiation potential, have however been found in umbilical cord blood [22–24]. These common lymphoid precursors (CLP) express lymphoid lineage specific genes [22,24]. In addition, CLP were identified by expression of the chemokine receptor CXCR4 on CD34+ cells in the bone marrow [25]. While multipotential hematopoietic progenitors are present in the thymus, it is still unknown whether lineage committed progenitors migrate to the thymus from the bone marrow. A simplified model of T-cell development in the thymus is shown in Fig. 3.

Different stages of T-cell development are characterized by changes in expression of cell surface molecules (Fig. 3) and gene expression (reviewed in [18]). Acquisition of CD1a expression on CD34+ cells in the thymus correlates with T-cell lineage commitment [26]. Immature thymocytes referred to as immature CD4 single positive cells (ISP), also called intrathymic T-cell progenitors (ITTP), express CD4 and are among the first cells to initiate rearrangement of TCR V-DJ gene segments. Upon productive TCRβ gene rearrangements, the cells express a pre-TCR on their cell surface, which consists of the TCRβ, pre-TCRα and CD3 proteins. Signaling via the pre-TCR allows for further development into the CD4+CD8+ double positive stage and initiation of TCRα rearrangements. During rearrangement of the TCRα genes, signal joint (sj) and coding joint (cj) gene TCR excision circles (TREC) are produced consisting of episomal DNA circles that are not replicated during mitosis and hence are diluted during proliferation [2] (reviewed in [27]). TREC generated during rearrangement of the TCRβ gene (β TREC) [28] appear at the CD34+CD1a+CD4+ ISP stage, before sj and cj TREC, allowing the assessment of the intra-thymic proliferation between these two rearrangements by the sj/βTREC ratio [29].

The thymic microenvironment ensures that after completion of the TCR rearrangements TCRα/β cells are either positively or negatively selected. Thymic epithelial cells play a key role in positive selection of TCRα/β cells, which is based on low affinity interactions of the TCRα/β with epithelial cells expressing major histocompatibility (MHC) antigens complexed with self-peptides. Thymic dendritic cells (DC) expressing high affinity self-peptide MHC complexes are essential for deletion of autoimmune cells in a process called negative selection (reviewed in [27]). Thymocytes at maturation stages after positive and negative selection are identified by the expression of CD27 and CD45RA and high levels of CD3/TCR (CD3/hi) similar to naive T cells present in cord blood (Fig. 3). While mature thymocytes expressing CD27 are mainly present in the thymic medulla, immature, CD1a expressing thymocytes are in the thymic cortex (Fig. 1).

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Cytokines in T-cell development

Although many cytokines are produced in the thymus, either by developing T cells or thymic stromal cells, interleukin (IL)-7 was identified as an essential cytokine for early human T-cell development [30,31]. IL-7 is produced by thymic epithelial cells and together with Notch, a regulator of transcription, promotes development of CD34+ cells into T lineage rather than myeloid lineage cells in the thymus [32]. The IL-7 receptor (IL-7R) consists of the IL-7Rα chain and the common γ (γc) chain. Expression of IL-7Rα chain is found at all stages of thymocyte maturation, although levels of expression vary [33]. Studies with exogenous IL-7 show that it induces proliferation and differentiation of developing thymocytes depending on their maturation stage [31,34,35] and may increase TREC in the thymus [33]. IL-7 may also play a role in expansion of recent thymic emigrants (RTE) in neonates while maintaining TREC frequencies [36,37]. It has been recently shown that IL-7 induced survival and proliferation of RTE are differentially regulated [38].

IL-7 is also essential for peripheral blood T-cell homeostasis (reviewed in [39]). Therefore, IL-7 therapy has been proposed as a means to improve T-cell reconstitution. Recently it has been shown that keratinocyte growth factor (KGF), which induces proliferation and differentiation of epithelial cells, improves T-cell reconstitution in rhesus macaques after autologous bone marrow transplantation [40], likely due to restoring IL-7 production by thymic epithelial cells [41].

SDF-1 renamed CXCL12 is produced by thymic epithelial cells and plays an important role in migration of immature progenitors in the thymus. CXCR4, the CXCL12 receptor and a HIV-1 coreceptor, is expressed on the majority of thymocytes at all stages of differentiation [42–47]. A synergistic effect of CXCL12 with IL-7 on survival of thymic progenitors has been reported [48].

The role of growth hormone (GH) and insuline like growth factor-I (IGF-1) in improving thymocyte proliferation and migration within the thymus is mainly based on animal studies (reviewed in [49]). GH-producing cells are found in the thymic capsule and subcapsular cortex [50]. In human studies GH induced an expansion of human fetal bone marrow CD34+ progenitor cells [51] and an increase in thymic mass and peripheral naïve CD4+ T cells in HIV-1-infected individuals [52].

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Thymus and aging

Thymic output of naive CD4+ and CD8+ T cells decreases with age. Normal functioning thymus tissue remains in adults, however, although a high inter-individual heterogeneity is observed [2,28,53–55]. Age-related changes in expression of cytokines have also been observed, although there was no correlation of IL-7 expression with age [56]. Decreased IL-7 expression was found in aged mice and could be restored by administration of KGF [57]. Thus, an impaired thymic micro-environment may be one of the factors playing a role in the decreased thymic output with age. A recent longitudinal study of individuals after autologous bone marrow transplantation showed the importance of the re-establishment of thymic function for naive T-cell reconstitution and a correlation between recovery of TREC+ peripheral naive T cells and TCR repertoire. The efficacy of immune reconstitution was inversely correlated with age and the level of recent thymic emigrants in the periphery directly correlated with thymic cellularity and volume [8].

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HIV-1 coreceptors in the thymus

Identification of the major co-receptors of HIV-1, CXCR4 and CCR5, in the mid-1990s [58–60] led several groups to determine the distribution of these chemokine receptors in the human thymus [42–47,61,62]. Several studies have shown that surface expression of both CXCR4 and CCR5 are modulated during thymocyte development [43,44,47]. Flow cytometric analysis of CXCR4 expression revealed widespread distribution of CXCR4 in the thymus [42,44] with the highest level of CXCR4 expression on immature CD3–CD4+CD8– ISP cells. CXCR4 is downregulated as thymocytes develop [43,44,47], but again upregulated just prior to emigration from the thymus [47]. In contrast to the abundance of CXCR4 in the thymus, CCR5 is expressed on a relatively small proportion of thymocytes. CCR5 is found on the surface of mature CD4 and CD8 single positive cells with the highest level on CD3+/hiCD27+CD45RA– thymocytes and in contrast to CXCR4 is slightly downregulated just prior to exiting the thymus [43,47]. CXCR4 and CCR5 are also expressed on small subsets of cells other than TCR α/β T cells, such as conventional dendritic cells (CD11c+), plasmacytoid dendritic cells (CD123++, BDCA-4+), CD161+ T cells, and γδT cells [63–66]. A much higher percentage of pDC express CCR5 (50 ± 36%) than thymocytes (0.1–2%) (Fig. 4) [64].

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Thymic targets of HIV infection

HIV-1 infection of the thymus in vivo has been confirmed in both the human and in the nonhuman primate model [67–69]. The dissemination of HIV-1 in the thymus is a consequence of the expression pattern of the primary HIV-1 coreceptors, CXCR4 and CCR5. It was recently shown that both CCR5 and CXCR4 tropic viruses can enter and complete reverse transcription in most thymocyte subsets [47]. Expression of viral proteins is, however, found within cell populations that express the highest levels of the appropriate coreceptor. Several studies have demonstrated that infection with CXCR4 tropic viruses leads to the productive infection of immature as well as mature thymocytes [43,44,46]. Although, immature thymocytes are preferentially depleted by CXCR4 tropic viruses because they express the highest level of CXCR4 [42,47], CXCR4 tropic HIV-1 infection leads to rapid depletion of all CD4+ cells located within the cortex and the medulla of the infected thymus [70,71]. As a consequence of the infection of immature thymocytes and subsequent thymocyte differentiation, HIV-1-infected CD8 single positive T cells are also found in the thymus [71,72]. In contrast, the kinetics of CCR5 infection is considerably slower than those of CXCR4 infection [70]. CCR5 tropic virus is primarily found within the medulla [43] and primary targets of CCR5 infection are mainly mature thymocytes [46,47,71]. Due to expression of both HIV-1 coreceptors conventional dendritic cells, plasmacytoid dendritic cells, CD161+ T cells, and γδ T cells can be infected by either CCR5 or CXCR4 tropic HIV-1 [63–66].

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The role of the thymus in HIV-1 immunopathogenesis

Impairment of thymic T-cell production in AIDS pathogenesis was proposed based on thymus pathology in AIDS patients which showed destruction of the thymic structure, a lack of thymocytes and infiltration of activated T cells [73,74]. However, prior to the progression of the disease to AIDS, studies of thymic function, as measured by output of naive T cells and the breadth of the TCR repertoire, did not confirm this thymic impairment. A study by Sopper et al. in the simian immunodeficiency virus (SIV)-infected rhesus macaque showed that while absolute numbers of CD4+ T cells are decreased in peripheral blood, there is a global increase in proliferation and in absolute CD4+ T-cell numbers in all lymphoid organs during the asymptomatic phase of the infection. In animals with symptoms of AIDS, however, the absolute numbers of CD4+ T cells in spleen and lymph nodes were not different from those of uninfected monkeys, but there was a drop in CD4+ T cells in the thymus and peripheral blood [75]. Although such a quantitative study cannot be performed in humans, clinical evidence like lymphadenopathy, the first recognized symptom of the disease, is suggestive of an accumulation of T cells in secondary lymphoid organs. An increase in T-cell numbers in lymphoid organs combined with the high T-cell turnover induced by the virus during the asymptomatic phase of HIV infection suggests that the thymus plays an important role in T-cell homeostasis during the asymptomatic phase of HIV-1 infection, in addition to homeostatic proliferative expansion (HPE) that takes place in the periphery.

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Thymectomy studies in HIV/simian immunodeficiency virus pathogenesis

Arron et al. studied thymic output in SIV infection in a group of thymectomized and sham-operated juvenile rhesus macaques. They concluded that thymic output in juvenile macaques has very little impact on the peripheral T-cell compartment, in both healthy and SIV-infected macaques [76]. Similar conclusions were drawn from observations in HIV-1-infected humans thymectomized for myasthenia gravis [73]. Some studies show, however, that thymectomy of uninfected children can indeed have an impact on the T-cell compartment later in life [77]. Moreover, in the context of bone-marrow transplantation, thymectomy studies demonstrate that the thymus is necessary to produce naïve CD4+CD45RA+ T cells [78,79]. The results of these thymectomy studies could be complicated by the presence of a cervical thymus [80,81] as a cervical thymus can be functional and produce a nonnegligible output of new T cells in a SIV-infected rhesus macaque [82]. Although cervical thymus tissue has been found in humans [83] such an observation has not yet been documented during HIV infection.

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Thymic output in disease progression

TREC have been found to be a good marker of thymic output in healthy individuals [84], but HIV-1 and more specifically the immune activation it induces complicate its use as a measure of the production of naive T cells. TREC are used to indirectly assess thymic output in humans and nonhuman primate models during HIV/SIV infections [2,85]. Douek et al. showed that sjTREC/μg DNA were significantly lower in both CD4+ and CD8+ T cells in blood and lymph nodes after HIV-1 infection compared to age-matched uninfected controls [2]. The TREC proportion among total peripheral blood mononuclear cells (PBMC) was found to be a marker of disease progression [86,87] and could also be used as a predictor of evolution of HIV-1 infection [88,89]. Similar results were observed in nonhuman primate models in which the decrease of TREC is correlated with the peripheral CD4+ T-cell decline [87]. Zhang et al. observed a progressive decrease in TREC/106 PBMC or values not different from the baseline levels, during a longitudinal analysis of 16 patients, pre and post-infection [55]. Therefore, these studies concluded that thymic production of T cells, as measured by the proportion of TREC+ T cells, was slowly impaired during HIV-1 infection.

Hazenberg et al. questioned the role of thymic output in HIV-1 infection by concluding that the rapid decline of percentages of sjTREC positive cells in a CD45RA+ population during the clinically asymptomatic phase of HIV-1 infection is due to the proliferation of T cells in the periphery [90]. The expression of the intra-nuclear protein Ki-67 is used as a measure of proliferation and is highly increased during a pathogenic HIV/SIV infection [91,92]. It has, however, been shown that Ki-67 is expressed in effector cells blocked in phase G1 of the cell cycle [93]. Therefore, the measurement of Ki-67 expression can be an over-estimation of T-cell proliferation when measured in bulk populations of PBMC or even in CD4+ or CD8+ T cells, leading to an under-estimation of thymic ouput measured by TREC. Moreover, the debate about the accuracy of TREC frequencies as a measurement of thymic output assessment was fed by the estimated longer life-span of RTE [94], which would impair the accurate measurement of thymic output. These estimations are based on long-term TREC detection after thymectomy in noninfected individuals, and on the assumption that these thymectomies were complete and that there is no other source of RTE than the thoracic thymus [81,82].

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Longitudinal and cross-sectional studies of treatment-naive simian immunodeficiency virus and HIV infection

Several studies in nonhuman primate models infected with SIV show that the levels of TREC+ T cells in peripheral blood can remain stable despite an increase in T-cell proliferation. In a longitudinal analysis of SIV-infected rhesus macaques Sodora et al. showed that during 16 to 30 weeks post-infection TREC frequencies remained stable or increased within both CD4+ and CD8+ T cells, despite an increase in T-cell proliferation, highly suggestive of an increase in thymic output. After 30 weeks, however, TREC frequencies declined suggesting thymic dysfunction [95]. Wykrzykowska et al. studied the impact of SIV on the thymus of rhesus macaques during the first 50 days of infection and found that pathogenic SIVmac239 infection induces an early rise in intrathymic proliferation with an increase in the size of the cortex and the percentage of CD34+ progenitor cells. The less pathogenic SIVmac239Δnef induced less dramatic effects with a rise in the percentage of CD34+ cells as early as 14 days post-infection [96]. In rhesus macaques infected with an attenuated virus, SIV251Δnef thymic function, measured by TREC+ naive T-cell numbers which is more appropriate than TREC frequencies [82], was increased in comparison with age-matched controls in all infected monkeys 8 years post-infection. However, persistent low level viral replication led to persistent low T-cell activation and depletion of CD4+ RTE from the blood and to the development of AIDS in some animals [97]. The depletion of CD4+ T cells is probably due to the trapping and death of CD4+ T cells in the secondary lymphoid organs [98]. Thymic cellularity and numbers of TREC+ CD4+CD45RA+ naive T cells negatively correlated with the rate of the disease progression [97]. In addition, during this infection, a higher rate of differentiation of naive cells towards the memory phenotype was observed as the number of TREC+CD45RA negative cells increased during the first 6 months of the infection (Unpublished data, R. Ho Tsong Fang and B. Hurtrel, Fig. 5). The surprisingly high numbers of TREC+CD45RA negative T cells in SIV251Δnef-infected macaques suggest a slower dilution of TREC interpreted as less proliferation during the differentiation process of naive T cells to the memory/effector cells than in uninfected monkeys. A high rate of differentiation of naive to memory T cells could explain the lack of correlation between TREC measurements and naive CD4+ T-cell counts after initiation of antiretroviral therapy [55] and confirms previous data of increased rates of differentiation [99]. This higher differentiation of naive T cells may be sustained by higher thymic output. The study performed by Sopper et al. showed that absolute numbers of total T cells as well as of CD3+/hiCD4+ and CD3+/hiCD8+ are increased in the thymus of asymptomatic rhesus macaques compared to age-matched controls [75].

The increase in thymic activity observed in the nonhuman primate models is consistent with results obtained in HIV-1 infection. Sustained TREC levels, despite an increase of peripheral T-cell proliferation, are present during early primary acute phase in humans (18–72 days after the onset of symptoms) and suggest a normal or increased thymic output during the acute phase of HIV infection [100]. TREC in purified CD4+ and CD8+ T cells were as well significantly increased compared to age-matched controls in patients under 45 years old during early infection (CD4 T-cell counts > 500 cells/μl) [101]. In addition, the presence of thymic tissue, determined by chest computed tomography, was significantly associated with both higher CD4+ T-cell counts and higher percentages and absolute numbers of naive CD45RA+CD62L+CD4+ T cells in HIV-1-infected adults suggesting increased thymic output [102]. Furthermore some younger adults had significantly more thymic tissue compared to noninfected subjects [102]. Dion et al. observed increased DβJβ TREC frequencies and absolute numbers in the peripheral blood of HIV-1-infected individuals compared to healthy controls, suggesting compensatory mechanisms to normalize thymic output [29]. These results from different studies during the clinically asymptomatic phase of the disease indicate that thymic output is normal or increased despite HIV-1 infection.

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The thymus during antiviral therapy

Studies of immune reconstitution during highly active antiretroviral therapy (HAART) show that the production of new T cells by the thymus is necessary for the reconstitution of a fully functional immune system. In the 1990s, the introduction of HAART dramatically decreased the incidence of AIDS, in particular due to immune reconstitution in treated patients. It is now clear, however, that the level of immune reconstitution is independent of the level of viral suppression and that AIDS is not purely a virological but also an immunopathological disease. The classification of different patterns of response to HAART elucidates distinct schemes of pathogenesis based on the rate of the loss of peripheral CD4+ T cells (Fig. 6).

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Immune reconstitution during HAART therapy

The results obtained in HAART-treated patients during the last 10 years show the thymus as a major organ involved in immune reconstitution. After the initiation of therapy, there is a biphasic recovery of CD4+ T cells; an early rise in memory CD4+ T cells is followed by a slow increase in naive T cells [103–105]. Smith et al. confirmed the kinetics of peripheral CD4+ T-cell recovery in people with a small thymus, but found that the primary rapid increase in naive T-cell numbers in individuals with abundant thymic tissue can be impaired by a rebound in viral replication [106]. This observation is consistent with a higher sensitivity of an active thymus to HIV-1 infection as demonstrated by high and persistent viral loads in infants [107] and high proportions of rapid HIV-1 disease in children [108].

In children, thymic function, and therefore immune reconstitution, after the initiation of HAART is better than in adults [109]. Reconstitution of naive CD4+CD45RA+CD62L+ T cells in HIV-infected children is correlated with an increase in thymus volume and a normalization of the CD4+ T-cell repertoire [110]. Lee et al. found that young adults who are long-term nonprogressors of perinatal HIV infection exhibit similar thymic volumes, thymic index, naive CD4+ T-cell values and numbers of TREC compared to uninfected individuals, suggesting that antiretroviral therapy has prevented the loss of or allowed for the recovery of functional thymic tissues [10]. Figure 7 depicts a CT scan of an 18-year-old HIV-1-infected individual with a normal thymic volume after treatment with HAART.

Functional thymus tissue is present in some HIV-1-infected adults [102]. Restoration of thymic function has been observed in adults treated with HAART, including a normalization of the CD4+ T-cell receptor repertoire [106,111–115], which is likely due to thymic activity [116]. Moreover, in the case of thymus-dependent reconstitution, TREC levels correlate with TCR diversity [117]. Therefore, these data strongly suggest an active role of the thymus in HIV-infected children and adults during immune reconstitution under HAART. Several studies show that in the context of HAART there is an increase in thymic output and T-cell proliferation in adults compared to healthy age-matched controls and a major increase in the TREC frequencies among naive CD45RA+CD62L+CD4+ T cells in complete responders to HAART compared to age-matched controls. Moreover, this thymic rebound can be accompanied by an increased thymic size compared to age-matched controls [6]. Biopsy results revealed that the increase in thymus size reflects active thymopoiesis [118]. Other studies report correlations between thymic size, TREC levels and immune reconstitution [119–121]. Notably, some high TREC levels have been reported in patients after initiation of HAART, but without a detectable thoracic thymus [115]. This finding can be consistent with an extra-thymic source or redistribution of naive T cells and with the presence of an ectopic thymus [80] that could be more prevalent during immune reconstitution, when the thoracic thymus may already be involuted [82]. The level of T-cell production contributed by intrathymic T-cell proliferation independent from peripheral proliferation can be evaluated by measuring ratios of sj and TCRβ TREC and is increased in some adults treated with HAART [29,122]. Thus, an increase in the absolute numbers of TREC in the blood suggests an increase in thymic output [97] and is further supported by the increase in sj/β TREC ratios and the observed increase or maintenance of the thymic volume.

Using in vivo labeling with deuterated glucose some, but not all, patients demonstrate high levels of T-cell production 12 weeks after initiation of HAART [99] suggesting that intrathymic proliferation is inhibited by HIV-1 infection but can resume under HAART. The basis for the increased CD4+ T-cell numbers with HAART is greater production, with a surprisingly shorter half-life of circulating T cells [99,123]. By combining the 2H2O technique with 2H-glucose incorporation/die-away measurements, Hellerstein et al. reported higher replacement rates of naive T cells in untreated HIV-1 infections, but with considerable inter-individual variability. The rate of replacement of naive T-cells and T-cell life span return back to normal with HAART [5]. It is clear, however, that not all individuals are capable of rejuvenating their thymus during treatment.

Some studies could not implicate the thymus in the immune reconstitution after HAART [124], showing that in some patients, immune reconstitution might occur without a contribution from the thymus. If peripheral T-cell reconstitution occurred solely by homeostatic proliferative expansion (HPE), however, functional immune reconstitution and the T-cell repertoire would be impaired [125]. This can lead to immune restoration disease, which was diagnosed in a patient treated with HAART as an atypical presentation of opportunistic infections despite a decrease in the viral load and an increase in peripheral CD4+ T-cell counts, and was found to coincide with thymic dysfunction [126]. Conversely, impairment of proper negative selection of developing T cells coupled with a large increase in thymic output following HAART therapy can lead to autoimmune disease [127].

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The thymus in discordant immunological and virological responders

In some cases, patients treated with HAART experience an increase in peripheral CD4+ T cells without a significant reduction in viral loads demonstrating that replication of the virus is not the determining factor of disease progression [128]. These individuals are called discordant immunological responders. Protease inhibitor-resistant viruses from discordant immunological responders showed impaired replication in the thymus, and patients infected with these viruses had a higher frequency of abundant thymus than age-matched, noninfected controls [129]. These patients also show a correlation of TREC frequencies in CD45RA+CD4+ T cells as well as of the individual's age with the rise in CD4+ T-cell counts [130]. Discordant immunological responders are more often observed in infants than in adults and significantly higher rates of CD4+ T-cell recovery are likely due to more robust thymic function [107,131,132]. Although sustained thymic output may lead to an increase in viral replication by producing new target T cells, this is negligible compared to the beneficial effect of de novo production of naive T cells in terms of immune reconstitution [133,134]. In adults, discordant immunological responders have higher CD45RA+TREC+ numbers compared to nonresponders [135]. The discordant immunological responders also exhibit a higher intra-thymic proliferation as measured by the sj/βTREC ratio, compared to patients that are not treated or poor responders [136].

In contrast to discordant immunological responders discordant virological responders (good virological control but poor CD4+ T-cell reconstitution) show poor thymic function compared to complete responders [137]. This may be due to infection with viral strains that target the thymus. CXCR4 tropism and some viral factors like Nef have been implicated in the pathogenicity of the virus for the thymus [122,138].

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Impact of HIV-1 on the thymus: implications for potential therapy

In summary, several studies show an increase in the thymus size or TREC levels in some HIV-1-infected patients in the absence of antiretroviral therapy compared to age-matched, noninfected controls. Treatment with HAART has a positive effect on thymic output and T-cell reconstitution. Therefore, a combination of antiviral drugs with cytokines, growth factors, or potential gene therapy is indicated to increase development of naive T cells in patients who do not naturally raise their thymic production. Encouraging data have been obtained with IL-7, which can increase the number of peripheral T cells in the context of HIV infection. However, as IL-7 also induces an increase in T-cell proliferation, several studies did not conclude that IL-7 increased thymic output, although unchanged TREC frequencies may still reflect a greater thymic output [97,139,140]. Under HAART, short-term administration of IL-7 increases peripheral T-cell numbers and thymic function as measured by intrathymic proliferation [141]. However, the presence of increased IL-7 levels combined with a decrease in IL-7Rα expression on T cells during progressive disease in HIV-1 infection diminishes the potential benefit of exogenous IL-7 [142]. KGF and growth hormone are potential therapies currently under consideration to regenerate thymic function in HIV-1 infection. Administration of KGF, which restores the thymic microenvironment potentially through increasing endogenous IL-7 production by thymic epithelial cells, shows great promise [40]. Growth hormone is another candidate and has been used in HIV-1-infected subjects and resulted in an increase in thymic volume and naive CD4+ T cells [52]. Recent studies also point to the possibility of using sex steroid ablation to enhance T-cell reconstitution [143].

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Evaluation of the role of the thymus in HIV-1 pathogenesis is complicated by HIV-induced immune activation with concurrent T-cell proliferation, the lack of access to the thymus in HIV-1-infected subjects and the numerous possibilities for pathogenesis depending on differences between individuals and in the pathogenicity of virus isolates for the thymus. Although CXCR4-tropic isolates generally cause more CD4+ T-cell depletion in the thymus than CCR5-tropic viruses, tropism is not the only determinant of pathogenesis in the thymus, as some CCR5-tropic virus isolates may be quite pathogenic whereas protease inhibitor-resistant viruses are relatively nonpathogenic for the thymus [129,144]. In addition, HIV-1-induced immune activation leads to a higher rate of differentiation of naive cells into the effector/memory pool. Based on data in the literature, an increase in thymic activity seems to be instrumental in maintaining the peripheral CD4+ T cells during the asymptomatic phase of HIV infection and is undeniably required for efficient immune reconstitution with a broad TCR repertoire during antiretroviral treatment. Deciphering the mechanisms responsible for this increased T-cell production by the thymus during the asymptomatic phase of HIV-1 infection is a major challenge and questions will need to be addressed whether it is specific to the virus or is due to an immune response. Enhancing thymic function together with suppression of immune activation will be essential to restoring the function and breadth of the T-cell compartment of the cellular immune system during HIV-1 infection.

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The present study was supported in part by grants from the National Institutes of Health (AI 52002, AI 52833). The authors thank Beth Jamieson, Bianca Blom and Jay Levy for their critical comments and Paul Krogstad and Ines Bouchat for the CT scan figure.

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coreceptor; HIV-1; T-cell regeneration; thymocyte subsets; thymus

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