Current Opinion in HIV & AIDS:
The T cell in HIV infection and disease: Basic science
Estimating the role of thymic output in HIV infection
De Boer, Rob J
Theoretical Biology, Utrecht University, Utrecht, The Netherlands
Correspondence to Rob J. De Boer, Theoretical Biology, Padualaan 8, 3584 CH Utrecht, The Netherlands Tel: +31 30 253 7560; fax: +31 30 251 3655; e-mail: R.J.DeBoer@bio.uu.nl
Purpose of review: The mechanisms by which infection with CCR5 tropic HIV causes the depletion of naive CD4+ and CD8+ T cells are poorly understood. As HIV infection affects the thymus, one hypothesis is ‘reduced thymic output’. As HIV infection is associated with hyperactivation, another hypothesis is ‘depletion by activation’. The best technique that is currently available for measuring thymic output in humans is to quantify TCR excision circles (TRECs) in peripheral T cells. Unfortunately, TREC data are very difficult to interpret.
Recent findings: The depletion of memory CD4+ T cells can be accounted for by the massive infection of these cells in the gut and mucosal tissues. The major controversy therefore remains to explain the depletion of naive T cells. SIV infection of thymectomized and euthymic Rhesus macaques revealed important new insights into the effects of thymectomy and SIV infection on naive T cell depletion.
Summary: Changes in the TREC content, i.e. the average number of TRECs per cell, are confounded by changes in division rates. By also expressing TREC measurements in terms of total TREC numbers, one obtains a much more reliable indication of thymic production. The relatively rapid changes in TREC contents observed in subsets of HIV patients are best explained by changes in T cell division rates. Infection of the thymus is expected to play a role in the long-term depletion of naive T cells, but direct evidence remains scarce. Routinely measuring TREC totals, in addition to the TREC content and naive T cell counts, would help to finally sort this out.
Abbreviations RTE: recent thymic emigrant; TCR: T cell receptor; TREC: TCR excision circle.
Recent studies have provided important new insights in the loss of memory CD4+ T cells during HIV infection. Studying CD4+ T cell dynamics during acute and chronic infection in SIV-infected monkeys [1,2,3•,4••] and in HIV-infected human patients [5,6•–9•] demonstrated a massive loss of memory CD4+ T cells in the gut and mucosal tissues. This depletion is readily explained by the infection of memory CD4+ target cells [8•,9•], which in turn could explain the decrease in the CD4: CD8 ratio in memory T cells over the course of infection. Additionally, in monkeys, it has been shown that the depletion is specific, i.e. R5 virus largely depletes CD4+ CCR5+ memory cells, and it was suggested that the increased proliferation of CD4+ T cells in the lymphoid tissue is required to compensate for the loss of CD4+ CCR5+ memory T cells in the mucosa [4••]. For memory CD4+ T cells, this would bring us back to the ‘tap and drain’ model proposed by Ho et al. . Several studies have, however, shown that hyperactivation is not a homeostatic response that is driven by the depletion of T cells .
Depletion of memory CD4+ cells in the gut does not explain why both CD4+ and CD8+ naive T cells are depleted . The size of the thymus decreases with age  and although the remaining thymus tissue in human adults seems functional and essential for de-novo production of naive T cells [14–17], the daily production rate is small and seems fairly unimportant for maintaining a large naive T cell population. Thus, although it has clearly been demonstrated that SIV/HIV infection affects the thymus and can deplete CD4+ thymocytes [18–21,22•], it remains unclear how much this contributes to the depletion of naive T cell numbers.
Unfortunately, it is very difficult to estimate thymic naive T cell production in humans, and the best method that is currently available is the measurement of T cell receptor excision circles (TRECs) that are produced when thymocytes rearrange the α and β chain of the TCR. TRECs are long-lived circular DNA fragments that are passed on to one of the daughter cells during cell division. The fraction of cells expressing a TREC is therefore an indication of the number of divisions the cells have gone through after emigration from the thymus. Several studies have shown that in normal healthy individuals, the TREC content of the peripheral T cell population decreases one to two logs with increasing age [23–25,26•,27•], which is perfectly consistent with thymic involution and a compensatory homeostatic response [28,29]. When it was shown that the fraction of CD4+ T cells carrying TRECs is also decreased in HIV-infected patients [23,24,26•,30,31], this was taken as evidence for decreased thymic output in HIV-infected patients [23,30–33]. The increased rates of cell division that are typical for HIV infection, however, can also explain lowered TREC contents [24,28,31,34,35,36••]. I will review one mathematical model and discuss several sets of TREC data to argue that the interpretation of the TREC content is complicated and unreliable [28,35,37•]. Following the original suggestion by Lewin et al. , my major recommendation is to routinely report the total number of TRECs in the population. The combination of TREC totals, the TREC content of naive T cells, and naive T cell counts provides more reliable information on the thymic output and peripheral proliferation [22•,26•,31,38••].
Thanks to the mathematical simplicity [39•] of the model explained in Box 1, we were able to make a number of inferences that are independent of the exact parameters of the model [28,29] (see Fig. 1). First, in the absence of naive T cell division, i.e. when ρ(N) = 0, the steady state TREC content is that of an RTE, i.e. C = c. Thus, the fact that the TREC content declines with age strongly suggests that naive T cells divide while maintaining their naive phenotype [28,29], which is controversial. Second, in the absence of homeostasis, i.e. when the renewal and death rates are independent of the population size, the quasi steady state of the naive T cell population in Eq. (3a) becomes proportional to the thymic output. If this is substituted into Eq. (3c), the average TREC content will no longer depend on the thymic output, or on time. The fact that the TREC content declines with age therefore provides evidence that there is homeostasis in the naive T cell population [28,29], which is also controversial. Third, Eq. (3c) shows that increasing the division rate ρ(N) has a similar effect on the steady state TREC content C as decreasing the thymic output σ(t) (see Fig. 1). Observing reduced TREC contents in HIV+ patients that have increased cell division due to hyperactivation is therefore no evidence for reduced thymic output [24,28,29,31,34,35]. Finally, we have shown that the TREC content decreases slowly when thymic output is reduced because naive T cells are long-lived . Increasing the division rate decreases the TREC content more rapidly because it increases the turnover of this otherwise very slow population [28,35]. Interestingly, the quasi steady state of the total number of TRECs in the naive T cell population is independent of the division rate [see Eq. (3b)]. In the absence of major changes in the death rate, the total number of TRECs would provide a much better indicator of the thymic output than the TREC content . When the death rate increases, however, TREC totals decline and the TREC content increases [28,35] (see Fig. 1).
The predictions of this model that the TREC content decreases slowly after thymectomy and changes more rapidly when division rates change were confirmed shortly after the publication of the model [30,31,34]. Division rates and TREC contents in CD4+ and CD8+ T cells were studied longitudinally in HIV+ patients who either initiated therapy [31,34] or interrupted therapy . As predicted , rapid changes in the TREC content were associated with changes in T cell proliferation [30,31,34]. Douek et al.  argue that the rapid fall in the TREC content in the patients interrupting therapy is most likely due to increased proliferation because of the delayed effects of thymectomy on the TREC content. The support for this delayed effect of thymectomy came from a study of Myasthenia Gravis patients . We re-analysed these data by computing TREC totals, and found that these decline very slowly (De Boer R, Ribeiro R, unpublished results). TREC contents and naive T cell numbers were much more variable . In SIV-infected macaques, the TREC content of CD4+ and CD8+ T cells also remained stable for 20–34 weeks after infection, and a later decline was attributed to both increased proliferation and decreased thymic production .
The best confirmation that the TREC content changes only slowly after thymectomy came from a study in which Rhesus macaques were thymectomized and were sampled monthly for 1 year [36••]. In thymectomized monkeys, naive CD4+ T cells decline at a rate of 0.0017/day, and the TREC content declines at a rate of 0.0043/day [36••], which translates into half-lives of 408 and 161 days, respectively. After complete thymectomy, the TREC content therefore takes almost half a year to be reduced by 50%. The total number of TRECs in CD4+ and CD8+ T cells decayed with half-lives of 139 and 99 days, respectively (Ribeiro R, personal communication). The fact that the TREC totals decline faster than the naive T cells suggests that naive T cells are maintaining themselves by renewal, and that TREC totals provide the better estimate for the thymus output. Another study in macaques showed that the TREC content of peripheral T cells had declined more than 10-fold 1 year after thymectomy , which – for unknown reasons – is considerably faster than the 161-day half-life estimated by Arron et al. [36••].
SIV infection in thymectomized monkeys
If the depletion of naive T cells during SIV/HIV infection were largely due to a reduced thymic production by infection of the thymus, one would expect that SIV infection hardly increases the depletion rates of TRECs or naive T cells in thymectomized monkeys [43•]. SIV infection of thymectomized monkeys, however, decreased the half-life of naive CD4+ T cells from 408 to 131 days, and the half-life of the TREC content from 161 to 63 days [36••]. The corresponding half-lives in sham-operated SIV-infected macaques decreased from 693 to 385 days for the naive CD4+ T cells, and from 1155 to 165 days for the TREC content [36••]. The similarity between sham-operated SIV-infected monkeys and non-infected thymectomized monkeys seems consistent with an interpretation that the major effect of SIV infection is to strongly reduce thymic output. The fact that SIV infection of thymectomized monkeys further decreased the half-lives, however, demonstrates that peripheral processes play an important role in the depletion of naive T cells [43•].
By measuring the TREC content of CD4+ and CD8+ T cells in lymph nodes and blood of macaques, Sodora et al.  suggested that TREC+ naive T cells preferentially home to the lymphoid tissue. In HIV+ patients, it was shown that during the first weeks of therapy, the TREC content in peripheral blood rises, while that in lymphoid tissue declines . In mice, TREC+ naive T cells also seem to have different trafficking between the various lymphoid organs [38••]. Summarizing, the rapid redistribution of naive T cells during HIV infection  could contribute to the observed rapid changes in the TREC content, and further complicates the analysis of TREC data.
Can thymic production also be increased?
Most HIV+ patients have lower T cell TREC contents than healthy controls. Nobile et al. [26•], however, demonstrated that CD4+ T cells in young HIV patients with relatively high CD4+ T cell counts have an increased TREC content, and have increased TREC totals compared with healthy controls. The increased TREC totals seem a strong indication for increased thymus production. One possible caveat is that HIV+ patients with a high CD4 count may have had this larger thymus already before they were infected [22•,26•]. Indeed, high pre-infection CD4 T cell numbers and TREC contents are associated with slower CD4 T cell decline during HIV infection . Another study by Dion et al. [22•] developed a method for measuring the TRECs formed during rearrangement of the β chain of the TCR, and report that the total number of β TRECs is increased in HIV+ patients, irrespective of their age. A possible caveat is that β TRECs are very difficult to measure because they are present at very low frequencies. A third study reports that virologically suppressed HIV+ patients have a 10-fold higher TREC content in CD4+ T cells and a larger thymus than age-matched healthy controls [37•]. The number of naive CD4+ T cells, however, was lower than that in controls [37•,47•]. All authors agree on the complexity of interpretation of these data [26•,37•,47•], and we need more convincing evidence for ‘thymic rebound’ in HIV+ patients. The data on thymic rebound are further complicated by the recent demonstration that the protease inhibitors used in antiretroviral therapy markedly increase thymic output by reducing apoptosis .
The very recent suggestion [22•,47•] that a large fraction of the TRECs is contained in RTEs with a much higher turnover than truly naive T cells [49,50•] opens up the possibility of rapid changes in TRECs after changes in thymic output. We have tested this possibility by re-analysing the early drop in total TRECs in thymectomized macaques [36••] and in thymectomized Myasthenia Gravis patients , and failed to find evidence for a more rapid drop in TREC totals during the first month(s) after thymectomy (De Boer R, Ribeiro R, unpublished results). The role that RTEs play in TREC dynamics therefore remains an open question that deserves further attention.
Naive T cells are very diverse long-lived cells, which, in human adults, survive well in the presence of very low thymic production, or in thymectomized individuals, in the complete absence of a thymus. One would therefore not expect that decreased thymic production during HIV infection significantly affects naive T cell counts. Conversely, increasing the turnover of this otherwise long-lived population by hyperactivation is expected to have significant effects, even in the presence of a normal low thymic production. Indeed, most of the evidence for a significant effect of reduced thymic output on naive T cell counts during HIV infection is based on TREC contents which are notoriously difficult to interpret [28,35]. Thus, although there is convincing evidence that HIV infection affects thymic function [18–21,22•,41], it remains to be shown that this causes naive T cell depletion. It seems likely, however, that the depletion of naive T cells by hyperactivation makes the de-novo production of naive T cells during later stages of disease more and more important.
Thymectomy or SIV infection in juvenile macaques decreased the half-life of naive T cells from about 700 days to about 400 days [36••], and decimated the TREC content in 1 year , which is fast enough to explain the observed depletion rates of naive T cells in HIV-infected patients . Similarly, thymectomy in young children has a strong impact on the number of naive T cells and their TREC content [51•,52], and the TREC content markedly declines on a timescale of weeks . The effect of thymectomy in human adults seems much slower . In combination, these data confirm the consensus of a decreasing contribution of the thymus with age. Very little solid evidence exists, however, that adult thymectomy hardly affects naive T cell numbers. Frequent sampling of TREC totals, the TREC content and naive T cell numbers in patients undergoing thymectomy could help to finally sort this out.
Several authors have emphasized the complexity of interpreting TREC data because (a) naive T cells are long-lived, (b) TREC contents are diluted by division, (c) TREC contents increase by increased death, (d) TRECs are not always measured within the naive T cell population, and (e) TREC+ RTEs may preferentially home to lymphoid tissues [28,31,35,37•,38••,44] (Fig. 1). If a large fraction of the TRECs is contained in RTEs [22•], the complexity of interpreting TREC data will only increase because RTE are short-lived , their survival may depend on the size of naive T cell pool [22•,47•] and RTE may change their trafficking between peripheral immune organs [38••]. Although I strongly recommend to also measure TREC totals, even those have to be interpreted with caution: Chu et al. [38••] showed that IL-7 administration into thymectomized mice increased TREC totals in lymphoid organs. The seemingly so obvious interpretation of increased thymic output would be completely wrong.
I thank José Borghans, Ruy Ribeiro and Alan Perelson for critical reading of the manuscript, and thank the Dutch NWO (VICI grant 016.048.603) and the HFSP (grant RGP0010/2004) for financial support. This paper was written at the Santa Fe Institute.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 90–91).
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depletion of naive T cells; mathematical modeling; thymus; TRECs
© 2006 Lippincott Williams & Wilkins, Inc.
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