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
From the aDepartments of Microbiology, Immunology, and Molecular Genetics, 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: firstname.lastname@example.org
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 , 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.
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  (Fig. 1). Cortical and medullary thymic epithelial cells (TEC) are of endodermal origin and constitute the main components of the thymic microenvironment . 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 . 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 . 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 ) .
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 , others do not support this concept  (reviewed in ). 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 . 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 ). Acquisition of CD1a expression on CD34+ cells in the thymus correlates with T-cell lineage commitment . 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  (reviewed in ). TREC generated during rearrangement of the TCRβ gene (β TREC)  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 .
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 ). 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).
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 . 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 . 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 . 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 .
IL-7 is also essential for peripheral blood T-cell homeostasis (reviewed in ). 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 , likely due to restoring IL-7 production by thymic epithelial cells .
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 .
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 ). GH-producing cells are found in the thymic capsule and subcapsular cortex . In human studies GH induced an expansion of human fetal bone marrow CD34+ progenitor cells  and an increase in thymic mass and peripheral naïve CD4+ T cells in HIV-1-infected individuals .
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 . Decreased IL-7 expression was found in aged mice and could be restored by administration of KGF . 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 .
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 . 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) .
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 . 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 . CCR5 tropic virus is primarily found within the medulla  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].
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 . 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.
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 . Similar conclusions were drawn from observations in HIV-1-infected humans thymectomized for myasthenia gravis . Some studies show, however, that thymectomy of uninfected children can indeed have an impact on the T-cell compartment later in life . 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 . Although cervical thymus tissue has been found in humans  such an observation has not yet been documented during HIV infection.
Thymic output in disease progression
TREC have been found to be a good marker of thymic output in healthy individuals , 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 . 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 . 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 . 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 . 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 . 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 , 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].
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 . 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 . 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 , 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 . The depletion of CD4+ T cells is probably due to the trapping and death of CD4+ T cells in the secondary lymphoid organs . Thymic cellularity and numbers of TREC+ CD4+CD45RA+ naive T cells negatively correlated with the rate of the disease progression . 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  and confirms previous data of increased rates of differentiation . 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 .
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 . 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) . 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 . Furthermore some younger adults had significantly more thymic tissue compared to noninfected subjects . 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 . 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.
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).
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 . 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  and high proportions of rapid HIV-1 disease in children .
In children, thymic function, and therefore immune reconstitution, after the initiation of HAART is better than in adults . 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 . 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 . 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 . 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 . Moreover, in the case of thymus-dependent reconstitution, TREC levels correlate with TCR diversity . 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 . Biopsy results revealed that the increase in thymus size reflects active thymopoiesis . 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 . This finding can be consistent with an extra-thymic source or redistribution of naive T cells and with the presence of an ectopic thymus  that could be more prevalent during immune reconstitution, when the thoracic thymus may already be involuted . 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  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  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 . 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 , 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 . 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 . 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 .
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 . 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 . 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 . 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 . 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 .
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 . 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].
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 . 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 . 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 . 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 . Recent studies also point to the possibility of using sex steroid ablation to enhance T-cell reconstitution .
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.
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.
1. Kong FK, Chen CL, Six A, Hockett RD, Cooper MD. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc Natl Acad Sci U S A 1999; 96:1536–1540.
2. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al
. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396:690–695.
3. Rizk G, Cueto L, Amplatz K. Rebound enlargement of the thymus after successful corrective surgery for transposition of the great vessels. Am J Roentgenol Radium Ther Nucl Med 1972; 116:528–530.
4. Hellerstein MK. Measurement of T-cell kinetics: recent methodologic advances. Immunol Today 1999; 20:438–441.
5. Hellerstein MK, Hoh RA, Hanley MB, Cesar D, Lee D, Neese RA, McCune JM. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest 2003; 112:956–966.
6. Harris JM, Hazenberg MD, Poulin JF, Higuera-Alhino D, Schmidt D, Gotway M, McCune JM. Multiparameter evaluation of human thymic function: interpretations and caveats. Clin Immunol 2005; 115:138–146.
7. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al
. Age, Thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332:143–149.
8. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al
. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005; 115:930–939.
9. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al
. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med 2001; 194:1731–1741.
10. Lee JC, Boechat MI, Belzer M, Church JA, De Ville J, Nielsen K, et al
. Thymic volume, T-cell populations, and parameters of thymopoiesis in adolescent and adult survivors of HIV infection acquired in infancy. AIDS 2006; 20:667–674.
11. Crivellato E, Vacca A, Ribatti D. Setting the stage: an anatomist's view of the immune system. Trends Immunol 2004; 25:210–217.
12. Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 2006; 441:992–996.
13. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 2006; 441:988–991.
14. Haynes BF, Martin ME, Kay HH, Kurtzberg J. Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues. J Exp Med 1988; 168:1061–1080.
15. van Ewijk W, Hollander G, Terhorst C, Wang B. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 2000; 127:1583–1591.
16. Boehm T, Bleul CC. Thymus-homing precursors and the thymic microenvironment. Trends Immunol 2006; 27:477–484.
17. Weerkamp F, Baert MR, Brugman MH, Dik WA, de Haas EF, Visser TP, et al
. Human thymus contains multipotent progenitors with T/B lymphoid, myeloid, and erythroid lineage potential. Blood 2006; 107:3131–3137.
18. Blom B, Spits H. Development of human lymphoid cells. Annu Rev Immunol 2006; 24:287–320.
19. Weijer K, Uittenbogaart CH, Voordouw A, Couwenberg F, Seppen J, Blom B, et al
. Intrathymic and extrathymic development of human plasmacytoid dendritic cell precursors in vivo. Blood 2002; 99:2752–2759.
20. Haddad R, Guimiot F, Six E, Jourquin F, Setterblad N, Kahn E, et al
. Dynamics of thymus-colonizing cells during human development. Immunity 2006; 24:217–230.
21. Blom B, Res P, Noteboom E, Weijer K, Spits H. Prethymic CD34+ progenitors capable of developing into T cells are not committed to the T cell lineage. J Immunol 1997; 158:3571–3577.
22. Haddad R, Guardiola P, Izac B, Thibault C, Radich J, Delezoide AL, et al
. Molecular characterization of early human T/NK and B-lymphoid progenitor cells in umbilical cord blood. Blood 2004; 104:3918–3926.
23. Hao QL, Zhu J, Price MA, Payne KJ, Barsky LW, Crooks GM. Identification of a novel, human multilymphoid progenitor in cord blood. Blood 2001; 97:3683–3690.
24. Hoebeke I, De Smedt M, Stolz F, Pike-Overzet K, Staal FJ, Plum J, Leclercq G. T-, B- and NK-lymphoid, but not myeloid cells arise from human CD34(+)CD38(-)CD7(+) common lymphoid progenitors expressing lymphoid-specific genes. Leukemia 2007; 21:311–319.
25. Ishii T, Nishihara M, Ma F, Ebihara Y, Tsuji K, Asano S, et al
. Expression of stromal cell-derived factor-1/pre-B cell growth-stimulating factor receptor, CXC chemokine receptor 4, on CD34+ human bone marrow cells is a phenotypic alteration for committed lymphoid progenitors. J Immunol 1999; 163:3612–3620.
26. Galy A, Verma S, Barcena A, Spits H. Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J Exp Med 1993; 178:391–401.
27. Spits H. Development of alphabeta T cells in the human thymus. Nat Rev Immunol 2002; 2:760–772.
28. Poulin JF, Viswanathan MN, Harris JM, Komanduri KV, Wieder E, Ringuette N, et al
. Direct evidence for thymic function in adult humans. J Exp Med 1999; 190:479–486.
29. Dion ML, Poulin JF, Bordi R, Sylvestre M, Corsini R, Kettaf N, et al
. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity 2004; 21:757–768.
30. Plum J, De Smedt M, Leclercq G, Verhasselt B, Vandekerckhove B. Interleukin-7 is a critical growth factor in early human T-cell development. Blood 1996; 88:4239–4245.
31. Pallard C, Stegmann AP, van Kleffens T, Smart F, Venkitaraman A, Spits H. Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity 1999; 10:525–535.
32. Garcia-Peydro M, de Yebenes VG, Toribio ML. Notch1 and IL-7 receptor interplay maintains proliferation of human thymic progenitors while suppressing non-T cell fates. J Immunol 2006; 177:3711–3720.
33. Okamoto Y, Douek DC, McFarland RD, Koup RA. Effects of exogenous interleukin-7 on human thymus function. Blood 2002; 99:2851–2858.
34. Napolitano LA, Stoddart CA, Hanley MB, Wieder E, McCune JM. Effects of IL-7 on early human thymocyte progenitor cells in vitro and in SCID-hu Thy/Liv mice. J Immunol 2003; 171:645–654.
35. Vollger LW, Uittenbogaart CH. Interleukin-7 promotes the generation of phenotypically mature CD45RA positive human thymocytes in-vitro. Cytokine 1993; 5:157–168.
36. Hassan J, Reen DJ. Human recent thymic emigrants–identification, expansion, and survival characteristics. J Immunol 2001; 167:1970–1976.
37. Schonland SO, Zimmer JK, Lopez-Benitez CM, Widmann T, Ramin KD, Goronzy JJ, Weyand CM. Homeostatic control of T-cell generation in neonates. Blood 2003; 102:1428–1434.
38. Swainson L, Kinet S, Mongellaz C, Sourisseau M, Henriques T, Taylor N. IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway. Blood 2007; 109:1034–1042.
39. Fry TJ, Mackall CL. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 2005; 174:6571–6576.
40. Seggewiss R, Lore K, Guenaga FJ, Pittaluga S, Mattapallil J, Chow CK, et al
. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 2007; 110:441–449.
41. Min D, Taylor PA, Panoskaltsis-Mortari A, Chung B, Danilenko DM, Farrell C, et al
. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 2002; 99:4592–4600.
42. Kitchen SG, Zack JA. CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus. J Virol 1997; 71:6928–6934.
43. Berkowitz RD, Beckerman KP, Schall TJ, McCune JM. CXCR4 and CCR5 expression delineates targets for HIV-1 disruption of T cell differentiation. J Immunol 1998; 161:3702–3710.
44. Zaitseva MB, Lee S, Rabin RL, Tiffany HL, Farber JM, Peden KW, et al
. CXCR4 and CCR5 on human thymocytes: biological function and role in HIV-1 infection. J Immunol 1998; 161:3103–3113.
45. Zhang L, He T, Talal A, Wang G, Frankel SS, Ho DD. In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors: CXCR4, CCR3, and CCR5. J Virol 1998; 72:5035–5045.
46. Pedroza-Martins L, Gurney KB, Torbett BE, Uittenbogaart CH. Differential tropism and replication kinetics of human immunodeficiency virus type 1 isolates in thymocytes: coreceptor expression allows viral entry, but productive infection of distinct subsets is determined at the postentry level. J Virol 1998; 72:9441–9452.
47. Gurney KB, Uittenbogaart CH. Human immunodeficiency virus persistence and production in T-cell development. Clin Vaccine Immunol 2006; 13:1237–1245.
48. Hernandez-Lopez C, Varas A, Sacedon R, Jimenez E, Munoz JJ, Zapata AG, Vicente A. Stromal cell-derived factor 1/CXCR4 signaling is critical for early human T-cell development. Blood 2002; 99:546–554.
49. Savino W, Postel-Vinay MC, Smaniotto S, Dardenne M. The thymus gland: a target organ for growth hormone. Scand J Immunol 2002; 55:442–452.
50. Maggiano N, Piantelli M, Ricci R, Larocca LM, Capelli A, Ranelletti FO. Detection of growth hormone-producing cells in human thymus by immunohistochemistry and nonradioactive in situ hybridization. J Histochem Cytochem 1994; 42:1349–1354.
51. Hanley MB, Napolitano LA, McCune JM. Growth hormone-induced stimulation of multilineage human hematopoiesis. Stem Cells 2005; 23:1170–1179.
52. Napolitano LA, Lo JC, Gotway MB, Mulligan K, Barbour JD, Schmidt D, et al
. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 2002; 16:1103–1111.
53. Jamieson BD, Douek DC, Killian S, Hultin LE, Scripture-Adams DD, Giorgi JV, et al
. Generation of functional thymocytes in the human adult. Immunity 1999; 10:569–575.
54. Haynes BF, Sempowski GD, Wells AF, Hale LP. The human thymus during aging. Immunol Res 2000; 22:253–261.
55. Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, et al
. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med 1999; 190:725–732.
56. Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, et al
. Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 2000; 164:2180–2187.
57. Min D, Panoskaltsis-Mortari A, Kuro OM, Hollander GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007; 109:2529–2537.
58. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, et al
. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996; 381:661–666.
59. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al
. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381:667–673.
60. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane G protein-coupled receptor. Science 1996; 272:872–877.
61. Kitchen SG, Zack JA. Distribution of the human immunodeficiency virus coreceptors CXCR4 and CCR5 in fetal lymphoid organs: implications for pathogenesis in utero. AIDS Res Hum Retroviruses 1999; 15:143–148.
62. Zamarchi R, Allavena P, Borsetti A, Stievano L, Tosello V, Marcato N, et al
. Expression and functional activity of CXCR-4 and CCR-5 chemokine receptors in human thymocytes. Clin Exp Immunol 2002; 127:321–330.
63. Keir ME, Stoddart CA, Linquist-Stepps V, Moreno ME, McCune JM. IFN-alpha secretion by type 2 predendritic cells up-regulates MHC class I in the HIV-1-infected thymus. J Immunol 2002; 168:325–331.
64. Gurney KB, Colantonio AD, Blom B, Spits H, Uittenbogaart CH. Endogenous IFN-alpha production by plasmacytoid dendritic cells exerts an antiviral effect on thymic HIV-1 infection. J Immunol 2004; 173:7269–7276.
65. Schmitt N, Nugeyre MT, Scott-Algara D, Cumont MC, Barre-Sinoussi F, Pancino G, Israel N. Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection. AIDS 2006; 20:533–542.
66. Gurney KB, Yang OO, Wilson SB, Uittenbogaart CH. TCR gamma delta+ and CD161+ thymocytes express HIV-1 in the SCID-hu mouse, potentially contributing to immune dysfunction in HIV infection. J Immunol 2002; 169:5338–5346.
67. Joshi VV, Oleske JM, Saad S, Gadol C, Connor E, Bobila R, Minnefor AB. Thymus biopsy in children with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1986; 110:837–842.
68. Baskin GB, Murphey-Corb M, Martin LN, Davison-Fairburn B, Hu FS, Kuebler D. Thymus in simian immunodeficiency virus-infected rhesus monkeys. Lab Invest 1991; 65:400–407.
69. Papiernik M, Brossard Y, Mulliez N, Roume J, Brechot C, Barin F, et al
. Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. Pediatrics 1992; 89:297–301.
70. Jamieson BD, Pang S, Aldrovandi GM, Zha J, Zack JA. In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates. J Virol 1995; 69:6259–6264.
71. Uittenbogaart CH, Anisman DJ, Jamieson BD, Kitchen S, Schmid I, Zack JA, Hays EF. Differential tropism of HIV-1 isolates for distinct thymocyte subsets in vitro. Aids 1996; 10:F9–F16.
72. Lee S, Goldstein H, Baseler M, Adelsberger J, Golding H. Human immunodeficiency virus type 1 infection of mature CD3hiCD8+ thymocytes. J Virol 1997; 71:6671–6676.
73. Haynes BF, Hale LP, Weinhold KJ, Patel DD, Liao HX, Bressler PB, et al
. Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J Clin Invest 1999; 103:453–460.
74. Grody WW, Fligiel S, Naeim F. Thymus involution in the acquired immunodeficiency syndrome. Am J Clin Pathol 1985; 84:85–95.
75. Sopper S, Nierwetberg D, Halbach A, Sauer U, Scheller C, Stahl-Hennig C, et al
. Impact of simian immunodeficiency virus (SIV) infection on lymphocyte numbers and T-cell turnover in different organs of rhesus monkeys. Blood 2003; 101:1213–1219.
76. Arron ST, Ribeiro RM, Gettie A, Bohm R, Blanchard J, Yu J, et al
. Impact of thymectomy on the peripheral T cell pool in rhesus macaques before and after infection with simian immunodeficiency virus. Eur J Immunol 2005; 35:46–55.
77. Halnon NJ, Jamieson B, Plunkett M, Kitchen CM, Pham T, Krogstad P. Thymic function and impaired maintenance of peripheral T cell populations in children with congenital heart disease and surgical thymectomy. Pediatr Res 2005; 57:42–48.
78. Heitger A, Greinix H, Mannhalter C, Mayerl D, Kern H, Eder J, et al
. Requirement of residual thymus to restore normal T-cell subsets after human allogeneic bone marrow transplantation. Transplantation 2000; 69:2366–2373.
79. Heitger A, Neu N, Kern H, Panzer-Grumayer ER, Greinix H, Nachbaur D, et al
. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90:850–857.
80. Terszowski G, Muller SM, Bleul CC, Blum C, Schirmbeck R, Reimann J, et al
. Evidence for a functional second thymus in mice. Science 2006; 312:284–287.
81. von Boehmer H. Immunology. Thoracic thymus, exclusive no longer. Science 2006; 312:206–207.
82. Ho Tsong Fang R, Uittenbogaart CH, Hurtrel B. HIV and the hidden face of the thymus. AIDS 2006; 20:2240–2242.
83. Khariwala SS, Nicollas R, Triglia JM, Garabedian EN, Marianowski R, Van Den Abbeele T, et al
. Cervical presentations of thymic anomalies in children. Int J Pediatr Otorhinolaryngol 2004; 68:909–914.
84. Arellano MV, Ordonez A, Ruiz-Mateos E, Leal-Noval SR, Molina-Pinelo S, Hernandez A, et al
. Thymic function-related markers within the thymus and peripheral blood: Are they comparable? J Clin Immunol 2006; 26:96–100.
85. Sodora DL, Douek DC, Silvestri G, Montgomery L, Rosenzweig M, Igarashi T, et al
. Quantification of thymic function by measuring T cell receptor excision circles within peripheral blood and lymphoid tissues in monkeys. Eur J Immunol 2000; 30:1145–1153.
86. Hatzakis A, Touloumi G, Karanicolas R, Karafoulidou A, Mandalaki T, Anastassopoulou C, et al
. Effect of recent thymic emigrants on progression of HIV-1 disease. Lancet 2000; 355:599–604.
87. Richardson MW, Sverstiuk AE, Silvera P, Greenhouse J, Lisziewicz J, Lori F, et al
. T-cell receptor excision circles (TREC) in SHIV 89.6p and SIVmac251 models of HIV-1 infection. DNA Cell Biol 2004; 23:1–13.
88. Goedert JJ, O'Brien TR, Hatzakis A, Kostrikis LG. T cell receptor excision circles and HIV-1 2-LTR episomal DNA to predict AIDS in patients not receiving effective therapy. Aids 2001; 15:2245–2250.
89. van Asten L, Danisman F, Otto SA, Borghans JA, Hazenberg MD, Coutinho RA, et al
. Preseroconversion immune status predicts the rate of CD4 T cell decline following HIV infection. AIDS 2004; 18:1885–1893.
90. Hazenberg MD, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC, Boucher CA, et al
. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med 2000; 6:1036–1042.
91. Sachsenberg N, Perelson AS, Yerly S, Schockmel GA, Leduc D, Hirschel B, Perrin L. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med 1998; 187:1295–1303.
92. Monceaux V, Ho Tsong Fang R, Cumont MC, Hurtrel B, Estaquier J. Distinct cycling CD4(+)- and CD8(+)-T-cell profiles during the asymptomatic phase of simian immunodeficiency virus SIVmac251 infection in rhesus macaques. J Virol 2003; 77:10047–10059.
93. Combadere B, Blanc C, Li T, Carcelain G, Delaugerre C, Calvez V, et al
. CD4+Ki67+ lymphocytes in HIV-infected patients are effector T cells accumulated in the G1 phase of the cell cycle. Eur J Immunol 2000; 30:3598–3603.
94. Hazenberg MD, Borghans JA, de Boer RJ, Miedema F. Thymic output: a bad TREC record. Nat Immunol 2003; 4:97–99.
95. Sodora DL, Milush JM, Ware F, Wozniakowski A, Montgomery L, McClure HM, et al
. Decreased levels of recent thymic emigrants in peripheral blood of simian immunodeficiency virus-infected macaques correlate with alterations within the thymus. J Virol 2002; 76:9981–9990.
96. Wykrzykowska JJ, Rosenzweig M, Veazey RS, Simon MA, Halvorsen K, Desrosiers RC, et al
. Early regeneration of thymic progenitors in rhesus macaques infected with simian immunodeficiency virus. J Exp Med 1998; 187:1767–1778.
97. Ho Tsong Fang R, Khatissian E, Monceaux V, Cumont MC, Beq S, Ameisen JC, et al
. Disease progression in macaques with low SIV replication levels: on the relevance of TREC counts. AIDS 2005; 19:663–673.
98. Viollet L, Monceaux V, Petit F, Ho Tsong Fang R, Cumont MC, Hurtrel B, Estaquier J. Death of CD4+ T cells from lymph nodes during primary SIVmac251 infection predicts the rate of AIDS progression. J Immunol 2006; 177:6685–6694.
99. Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, et al
. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999; 5:83–89.
100. Sempowski GD, Hicks CB, Eron JJ, Bartlett JA, Hale LP, Ferrari G, et al
. Naive T cells are maintained in the periphery during the first 3 months of acute HIV-1 infection: implications for analysis of thymus function. J Clin Immunol 2005; 25:462–472.
101. Nobile M, Correa R, Borghans JA, D'Agostino C, Schneider P, De Boer RJ, Pantaleo G. De novo T-cell generation in patients at different ages and stages of HIV-1 disease. Blood 2004; 104:470–477.
102. McCune JM, Loftus R, Schmidt DK, Carroll P, Webster D, Swor-Yim LB, et al
. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest 1998; 101:2301–2308.
103. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al
. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277:112–116.
104. Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, et al
. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med 1998; 4:208–214.
105. Zhang ZQ, Notermans DW, Sedgewick G, Cavert W, Wietgrefe S, Zupancic M, et al
. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc Natl Acad Sci U S A 1998; 95:1154–1159.
106. Smith KY, Valdez H, Landay A, Spritzler J, Kessler HA, Connick E, et al
. Thymic size and lymphocyte restoration in patients with human immunodeficiency virus infection after 48 weeks of zidovudine, lamivudine, and ritonavir therapy. J Infect Dis 2000; 181:141–147.
107. Krogstad P, Uittenbogaart CH, Dickover R, Bryson YJ, Plaeger S, Garfinkel A. Primary HIV infection of infants: the effects of somatic growth on lymphocyte and virus dynamics. Clin Immunol 1999; 92:25–33.
108. Pizzo PA and Wilfret CM. Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents,
3rd edn. Baltimore, MD: Williams and Wilkins; 1998.
109. Resino S, Seoane E, Perez A, Ruiz-Mateos E, Leal M, Munoz-Fernandez MA. Different profiles of immune reconstitution in children and adults with HIV-infection after highly active antiretroviral therapy. BMC Infect Dis 2006; 6:112.
110. Vigano A, Vella S, Principi N, Bricalli D, Sala N, Salvaggio A, et al
. Thymus volume correlates with the progression of vertical HIV infection. AIDS 1999; 13:F29–F34.
111. Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, et al
. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 1998; 4:215–221.
112. Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, et al
. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997; 3:533–540.
113. Cossarizza A, Poccia F, Agrati C, D'Offizi G, Bugarini R, Pinti M, et al
. Highly active antiretroviral therapy restores CD4+ Vbeta T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection. J Acquir Immune Defic Syndr 2004; 35:213–222.
114. Hardy G, Worrell S, Hayes P, Barnett CM, Glass D, Pido-Lopez J, et al
. Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection. HIV Med 2004; 5:67–73.
115. Fernandez S, Nolan RC, Price P, Krueger R, Wood C, Cameron D, et al
. Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy. AIDS Res Hum Retroviruses 2006; 22:163–170.
116. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156:4609–4616.
117. Sarzotti M, Patel DD, Li X, Ozaki DA, Cao S, Langdon S, et al
. T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol 2003; 170:2711–2718.
118. Markert ML, Alvarez-McLeod AP, Sempowski GD, Hale LP, Horvatinovich JM, Weinhold KJ, et al
. Thymopoiesis in HIV-infected adults after highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2001; 17:1635–1643.
119. Ruiz-Mateos E, Rubio A, Vallejo A, De la Rosa R, Sanchez-Quijano A, Lissen E, Leal M. Thymic volume is associated independently with the magnitude of short- and long-term repopulation of CD4+ T cells in HIV-infected adults after highly active antiretroviral therapy (HAART). Clin Exp Immunol 2004; 136:501–506.
120. Franco JM, Rubio A, Martinez-Moya M, Leal M, Merchante E, Sanchez-Quijano A, Lissen E. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 2002; 99:3702–3706.
121. Delgado J, Leal M, Ruiz-Mateos E, Martinez-Moya M, Rubio A, Merchante E, et al
. Evidence of thymic function in heavily antiretroviral-treated human immunodeficiency virus type 1-infected adults with long-term virologic treatment failure. J Infect Dis 2002; 186:410–414.
122. Delobel P, Nugeyre MT, Cazabat M, Sandres-Saune K, Pasquier C, Cuzin L, et al
. Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy. J Virol 2006; 80:10229–10236.
123. McCune JM, Hanley MB, Cesar D, Halvorsen R, Hoh R, Schmidt D, et al
. Factors influencing T-cell turnover in HIV-1-seropositive patients. J Clin Invest 2000; 105:R1–R8.
124. Pido-Lopez J, Burton C, Hardy G, Pires A, Sullivan A, Gazzard B, et al
. Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune). AIDS Res Hum Retroviruses 2003; 19:103–109.
125. Walker RE, Carter CS, Muul L, Natarajan V, Herpin BR, Leitman SF, et al
. Peripheral expansion of preexisting mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults. Nat Med 1998; 4:852–856.
126. Gutierrez S, Alconchel S, Ruiz-Mateos E, Genebat M, Vallejo A, Lissen E, et al
. Disseminate and fatal cytomegalovirus disease with thymitis in a naive HIV-patient after early initiation of HAART: immune restoration disease? J Clin Virol 2006; 36:13–16.
127. French MA, Lewin SR, Dykstra C, Krueger R, Price P, Leedman PJ. Graves' disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymic dysfunction. AIDS Res Hum Retroviruses 2004; 20:157–162.
128. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet 1998; 351:723–724.
129. Stoddart CA, Liegler TJ, Mammano F, Linquist-Stepps VD, Hayden MS, Deeks SG, et al
. Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nat Med 2001; 7:712–718.
130. Lecossier D, Bouchonnet F, Schneider P, Clavel F, Hance AJ. Discordant increases in CD4+ T cells in human immunodeficiency virus-infected patients experiencing virologic treatment failure: role of changes in thymic output and T cell death. J Infect Dis 2001; 183:1009–1016.
131. Cohen Stuart JW, Slieker WA, Rijkers GT, Noest A, Boucher CA, Suur MH, et al
. Early recovery of CD4+ T lymphocytes in children on highly active antiretroviral therapy. Dutch study group for children with HIV infections. AIDS 1998; 12:2155–2159.
132. Essajee SM, Kim M, Gonzalez C, Rigaud M, Kaul A, Chandwani S, et al
. Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children. AIDS 1999; 13:2523–2532.
133. Saitoh A, Singh KK, Sandall S, Powell CA, Fenton T, Fletcher CV, et al
. Association of CD4+ T-lymphocyte counts and new thymic emigrants in HIV-infected children during successful highly active antiretroviral therapy. J Allergy Clin Immunol 2006; 117:909–915.
134. De Rossi A, Walker AS, De Forni D, Klein N, Gibb DM. Relationship between changes in thymic emigrants and cell-associated HIV-1 DNA in HIV-1-infected children initiating antiretroviral therapy. Antivir Ther 2005; 10:63–71.
135. Solomon A, Cameron PU, Bailey M, Dunne AL, Crowe SM, Hoy JF, Lewin SR. Immunological and virological failure after antiretroviral therapy is associated with enhanced peripheral and thymic pathogenicity. J Infect Dis 2003; 187:1915–1923.
136. Dion ML, Bordi R, Zeidan J, Asaad R, Boulassel MR, Routy JP, et al
. Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection. Blood 2007; 109:2912–2920.
137. Teixeira L, Valdez H, McCune JM, Koup RA, Badley AD, Hellerstein MK, et al
. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. AIDS 2001; 15:1749–1756.
138. Duus KM, Miller ED, Smith JA, Kovalev GI, Su L. Separation of human immunodeficiency virus type 1 replication from nef-mediated pathogenesis in the human thymus. J Virol 2001; 75:3916–3924.
139. Storek J, Gillespy T 3rd, Lu H, Joseph A, Dawson MA, Gough M, et al
. Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys. Blood 2003; 101:4209–4218.
140. Fry TJ, Moniuszko M, Creekmore S, Donohue SJ, Douek DC, Giardina S, et al
. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003; 101:2294–2299.
141. Beq S, Nugeyre MT, Ho Tsong Fang R, Gautier D, Legrand R, Schmitt N, et al
. IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J Immunol 2006; 176:914–922.
142. Albuquerque AS, Cortesao CS, Foxall RB, Soares RS, Victorino RM, Sousa AE. Rate of increase in circulating IL-7 and loss of IL-7Ralpha expression differ in HIV-1 and HIV-2 infections: two lymphopenic diseases with similar hyperimmune activation but distinct outcomes. J Immunol 2007; 178:3252–3259.
143. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, et al
. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005; 175:2741–2753.
144. Pedroza-Martins L, Boscardin WJ, Anisman-Posner DJ, Schols D, Bryson YJ, Uittenbogaart CH. Impact of cytokines on replication in the thymus of primary human immunodeficiency virus type 1 isolates from infants. J Virol 2002; 76:6929–6943.
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© 2008 Lippincott Williams & Wilkins, Inc.
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