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*
Vaccine Research Center and
Laboratory of Immunoregulation, Clinical and Molecular Retrovirology Section, National Institute of Allergy and Infectious Diseases,
Department of Experimental Transplantation and Immunology, Medicine Branch, National Cancer Institute, and
Critical Care Medicine Department, Warren Magnusen Clinical Center, National Institutes of Health, Bethesda, MD 20892;
¶ Department of Medicine, University of California, San Diego, CA 92103;
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Science Applications International Corporation-Frederick, Clinical Services Program, Frederick Cancer Research and Development Center, Frederick, MD 21702;
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Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
**
San Diego Veterans Affairs Medical Center, La Jolla, CA 92093
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vivo bromodeoxyuridine (BrdU) incorporation studies in SIV-infected monkeys showed increased turnover in all T cell populations, with memory T cells affected more than naive (7, 30). Studies using expression of the Ki67 nuclear Ag as a marker of cell proliferation indicated that total T cell turnover increased in naive and memory subsets during infection (31). This suggested that CD4+ T cell loss was due to interference of the virus with "T cell renewal capacity" rather than with peripheral production, and that redistribution accounted for increased CD4+ T cell numbers during treatment (31). However, a more recent study (32) also using Ki67 showed that turnover rate, but not proliferation, increased in CD4+ T cells, suggesting their increased death and decreased renewal (32). In vivo labeling with deuterated glucose confirmed some of these findings, showing that HIV infection caused a decrease in memory (but not naive) CD4+ and CD8+ T cell half-life with a compensatory increase in production of CD8+ but not CD4+ T cells (33).
The measurement of TCR rearrangement excision circles (TREC) has been used to assess thymic output in individuals with and without HIV infection (23, 26, 34, 35, 36, 37), and after hematopoietic stem cell transplantation (29, 38, 39). In the majority of individuals with untreated HIV-infection, TREC levels were below normal, but increased after viral suppression with HAART (23, 26, 37). This was taken to indicate that the thymus, in both adults and children, is suppressed by HIV infection, but contributes to T cell reconstitution during HAART. In this study, we sought to determine whether increased T cell turnover, decreased thymic output, or both occur in HIV infection. We measured peripheral blood TREC levels and parameters of CD4+ and CD8+ T cell proliferation, including Ki67 expression and ex vivo BrdU incorporation, in 22 individuals with early untreated HIV disease (3–12 mo after infection), and in 15 successfully treated HIV-infected individuals who underwent temporary interruption of therapy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-two patients with early HIV infection (3–12 mo after seroconversion) were seen at the University of Texas Southwestern Medical Center and had not been on antiretroviral drugs at the time of blood draw. CD4+ T cell counts were 220-1080 cells/µl (mean 602) and viral loads were <400 to >7.5 x 104 RNA copies/ml. Fifteen patients were asymptomatic HIV-infected adults with baseline CD4+ T cell counts of >350 cells/µl who had been on continuous HAART for a minimum period of 1 year, with viral loads consistently below the limits of detection for at least that period of time (40). On day 0, patients discontinued all antiretroviral drugs, and resumed drugs when any of the following three conditions was met: the CD4+ T cell count declined at least 25% from the mean of three baseline determinations, their viral load increased to 5000 RNA copies/ml, or the patient resumed drug treatment independently. Viral loads were measured by Amplicor assay (Roche, Basel, Switzerland). Studies were approved by the Institutions’ review boards, and patients gave informed consent.
Measurement of TREC in MACS-sorted cells
Quantification of TREC in sorted CD4+ and
CD8+ T cells was performed by quantitative PCR
with an ABI7700 system (PerkinElmer/Cetus, Norwalk, CT) as previously
described (29). PBMC were separated into
CD4+ and CD8+ cells using
MACS microbeads (Miltenyi Biotec, Auburn, CA). Cells were lysed in
proteinase K (Boehringer Mannheim, Indianapolis, IN) and PCR was
performed on 5 µl of cell lysate (50,000 cells). A standard curve was
plotted, and TREC values for samples were calculated by the ABI7700
software. Samples were analyzed in duplicate. TREC levels are expressed
as TREC per microgram of DNA (1 µg of genomic DNA is equivalent to
150,000 cells). Cell lysates have been checked for consistency of DNA
content using 
-actin and CCR5 control PCR; interassay variability
was found to be less than 13% of mean for the same sample in 20
different assays (data not shown).
Ex vivo BrdU uptake analysis
Blood samples were incubated with 100 µM BrdU for 4 h at 37°C. Cell surface staining was performed using Abs to CD3, CD45RO, CD4, and/or CD8 (BD Biosciences, San Jose, CA). Cells were treated with OptiLyse (Immunotech, Westbrook, ME) for 10 min at room temperature, then with 1% paraformaldehyde and 1% Tween 20 in PBS for 15 min at 37°C. Cellular DNA was denatured with 100U DNase-I (Boehringer Mannheim) for 30 min and was then stained with anti-BrdU-FITC (BD Biosciences). Events (50,000–100,000) were collected flow cytometrically, resulting in a sensitivity of 0.01% BrdU+ events, and were analyzed in parallel with unlabeled cells from the same individual and this value was subtracted from the value obtained for BrdU-labeled cells. Data are expressed as the fold change in the percentage of BrdU+ cells to avoid large baseline differences in absolute values between individuals. However, similar statistical significance was obtained when the fold change in absolute BrdU+ cells was used (data not shown).
Naive T cell Ki67 analysis and FACS sorting
Analysis was performed by surface staining cells for either CD4/CD45RO/CD27 or CD8/CD45RO/CD27 (BD Biosciences), followed by fixation/permeabilization and intracellular staining for Ki67 (BD Biosciences). Cells were analyzed by four-color flow cytometry using a FACSCalibur. Ki67 expression was measured in both CD45RO-CD27high (naive) and CD45RO+ (memory/effector) CD4+ and CD8+ T cells using Paint-a-Gate cluster analysis. For FACS sorting of naive and memory T cells, cells were stained as above (but without Ki67), and were sorted for TREC analysis using a FACSort (BD Biosciences).
Statistical analyses
Two-tailed Mann-Whitney U test and Spearman’s rank correlation coefficients were performed using SAS and Prism software (SAS Institute, Cary, NC). Analysis of covariance was used to assess differences in CD4+ and CD8+ T cell TREC between HIV-infected individuals and the healthy controls, adjusting for age. A p value of <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TREC frequency in total and in naive T cells has been shown to
decrease with age, after thymectomy, and in HIV infection (23, 26, 34, 35, 36, 41). However, a recent mathematical model has
suggested that this decrease in TREC solely reflects a theoretical
increase in the naive T cell division rate, and not decreased
thymic output (42). Therefore, we sought to test this
experimentally by measuring changes in T cell division with age using
Ki67 expression as a surrogate marker of cell proliferation. Fig. 1
shows that Ki67 expression does
not increase in either CD4+ or
CD8+CD45RO-CD27high
(naive) T cells in healthy individuals aged between 23 and 88 years of
age (during which period the most rapid drop in naive T cell TREC is
seen; Refs. 23 and 26). Furthermore, it has
recently been shown that although TREC decrease after thymectomy, there
is no increase in CD27high (naive) or
CD45RO+ memory T cell Ki67 expression
(41). The fact that Ki67 may be raised in nonproliferating
or activated cells (3, 43) does not affect this analysis
because the aim in this study was to exclude any increases in
proliferation. Thus, a decrease in TREC levels can indeed reflect a
decrease in thymic output.
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It has recently been shown that after total thymectomy, TREC levels begin to fall after only 3 mo (41). Therefore, in HIV infection, any decrease in TREC related to decreased thymic output would not be expected to be observed until at least 3 mo after seroconversion. Consequently, decreases in TREC before 3 mo of HIV infection would reflect primarily increased T cell proliferation.
To examine this, we initially studied T cell TREC levels in 15
HIV-infected individuals who had been successfully treated with HAART,
had undetectable viral loads, and then underwent interruption of
therapy (40, 44). As previously reported, recrudescence of
viral replication occurred in all the patients within 28 days of
interruption of therapy. This allowed us to longitudinally assess
changes in TREC and proliferation during a rapid rise in HIV levels—a
situation reminiscent of acute HIV infection. As viral load rose, both
CD4+ and CD8+ T cell TREC
levels decreased concomitantly. We then performed ex vivo BrdU
incorporation to determine whether this fall in TREC was, in part,
secondary to increased T cell proliferation. The correlation between
the S-phase BrdU fraction and viral load has been previously described
(44). In the interval between interruption and resumption
of therapy, there was a significant negative correlation between the
change in the percentage of
BrdU+CD4+ T cells and the
change in CD4+ T cell TREC levels
(r = -0.6, p = 0.02, and 95%
confidence interval = -0.86 to -0.09; Fig. 2). Thus, as CD4+ T
cell proliferation increased with a concomitant increase in viral load
(40), TREC levels decreased. The change in the percentage
of BrdU+CD8+ T cells also
varied inversely with the change in CD8+ T cell
TREC levels. However, this relationship was not statistically
significant for this sample size (r = -0.3,
p = 0.3, and 95% confidence interval =
-0.72–0.31), and a larger study sample would be required to establish
a statistically significant relationship. It is a possibility that
preferential redistribution of TREC-containing cells out of the
peripheral circulation could cause the decrease in TREC. Of course,
these data do not rule out a concomitant decrease in thymic output; it
is simply not possible to differentiate the effects of thymic output
and T cell proliferation. However, bearing in mind the delayed effects
of thymectomy on TREC levels (41), the rapid fall in TREC
during an acute rise in HIV load more likely reflects increased T cell
proliferation than decreased thymic output.
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Inhibition of thymic function should become detectable by 3 mo after HIV infection. To differentiate experimentally between thymic inhibition and increased peripheral T cell proliferation, it is necessary to measure an independent marker of T cell proliferation in naive and memory T cells, and to measure or calculate the TREC content of the naive T cell pool. If naive T cell proliferation is constant, then changes in TREC levels reflect changes in the supply of naive T cells. Therefore, we measured TREC levels and Ki67 expression in naive and memory CD4+ and CD8+ T cell subsets in a separate group of 22 patients with early (3–12 mo after seroconversion) untreated HIV infection. Ki67 expression was used, rather than BrdU incorporation, because these were cryopreserved samples. It should be stressed, however, that the number of Ki67+ cells and the S-phase fraction (BrdU+ cells after a 4-h in vitro pulse) are not equivalent measures of T cell activation, and many more cells express Ki67 than are actually in S-phase at any particular instant in time. The longevity of Ki67 expression after mitosis remains unclear.
Fig. 3 shows that both
CD4+ and CD8+ T cell TREC
were significantly lower than in uninfected age-matched controls
(p = 0.008 and 0.001, respectively). For
measurement of Ki67 expression in naive and memory T cells, subsets
were very carefully defined so that the naive subset would contain few
cells outside the
CD27+CD45RO- population.
Fig. 4 shows that the percentage of
Ki67+CD4+ and
Ki67+CD8+CD45RO+
(memory) T cells was significantly increased in HIV-infected
individuals compared with uninfected individuals (5.7-fold and
6.9-fold, respectively; p < 0.0001 for both). We also
confirmed that the percentage of
Ki67+CD45RO+ (memory) T
cells was significantly higher than that of naive T cells within the
infected and uninfected groups (CD4, 17.4-fold and p <
0.0001; CD8, 5.2-fold and p = 0.0003; CD4, 1.9-fold and
p = 0.0031; CD8, 2.7-fold and p =
0.0017, infected and uninfected, respectively). However, although the
percentage of
Ki67+CD8+CD45RO-CD27high
(naive) T cells was also significantly increased in HIV-infected
individuals (3.6-fold, p = 0.0002), the percentage of
Ki67+CD4+CD45RO-CD27high
(naive) T cells did not differ significantly from uninfected
individuals (p = 0.064), and was in fact
slightly lower. Thus, even though Ki67 expression may indicate T cell
proliferation and/or activation, these data suggested that the decrease
in CD4+ T cell TREC during HIV infection could
not be the result of increased turnover of naive
CD4+ T cells.
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Although we found no increase in naive CD4+
T cell Ki67 expression in early HIV infection, other studies have shown
it to be increased (31). The phenotypic definition of
naive T cells as
CD45RO-CD27high by flow
cytometry reveals that HIV-infected subjects contain more T cells with
a phenotype between that of true naive and effector/memory cells than
uninfected individuals (Fig. 5). These
have been termed "transitional" cells (45). Therefore,
we reanalyzed the data shown in Fig. 4
, incorporating a small
proportion of transitional CD4+ T cells into the
naive T cell gate, and then measuring Ki67 expression. We found that
the inclusion of only 5% more transitional cells apparently increased
naive CD4+ T cell Ki67 expression 4.7-fold (range
4–16) in the HIV-infected subjects, but only 1.7-fold (range 1.3–2.2)
in the uninfected subjects. This difference was statistically
significant (p = 0.01), and leads to the
misleading conclusion that naive CD4+ T cell Ki67
expression is increased in HIV-infected individuals. An example of the
effect of inclusion of transitional T cells on naive
CD4+ T cell Ki67 expression is shown in Fig. 5.
These T cells may have recently been naive cells that are transitioning
to activated cells and that will proliferate. Thus, accurate
measurement of activation and proliferation in naive
CD4+ T cells requires rigorous phenotypic
definition of this population by flow cytometry.
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Therefore, to determine whether thymic output was decreased in
early HIV infection in the context of unchanged naive
CD4+ T cell proliferation (and also to exclude
memory T cell expansions as a cause of decreased total T cell TREC), we
calculated naive T cell TREC from the total measured TREC and the
percentage of naive T cells determined by flow cytometry. Our
calculation assumed that the contribution of TREC from memory T cells
was negligible. This is a valid assumption, as we have measured TREC in
highly FACS-purified CD4+ T cell populations from
12 individuals and have found that CD45RO+
(memory) T cells have, on average, only 2% of the TREC content of
CD45RO-CD27high (naive) T
cells in the same individual. Furthermore, as an example of the
concordance between calculated and actual measured naive T cell TREC,
we FACS sorted
CD45RO-CD27high (naive) T
cells in one individual, measured TREC directly, and compared this
result with TREC calculated from unsorted T cells and the naive T cell
percentage, as shown in Tables I and II.
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a). Because the percentage of
Ki67+CD8+CD45RO-CD27high
(naive) T cells was increased in HIV-infected individuals, the reduced
naive CD8+ TREC levels could have been solely or
partly due to increased naive CD8+ T cell
proliferation. However, the percentage of
Ki67+CD4+CD45RO-CD27high
(naive) T cells was not increased, and therefore, the decrease in TREC
within CD45RO-CD27high
(naive) CD4+ T cells could not have been due to
increased proliferation of cells in this compartment. This suggests
that the decreased naive CD4+ T cell TREC levels
caused by HIV infection should be reversible when virus replication is
suppressed. To confirm this, we longitudinally followed, after
initiation of HAART, the
CD45RO-CD27high (naive)
CD4+ T cell TREC levels of five patients who had
low TREC before therapy. After initiation of HAART, which reduced viral
loads to undetectable levels,
CD45RO-CD27high (naive)
CD4+ T cell TREC rose to normal levels,
suggesting that changes in thymic output were responsible for the
changes in TREC within the naive CD4+ T cells
before and after HAART (Fig. 6b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The measurement of peripheral blood TREC provides insight into both thymic function and T cell proliferation. If naive T cell TREC levels decrease in the absence of an increase in proliferation, it may be concluded that there is a decrease in the supply of new TREC+ cells, most likely from the thymus. In this study, we aimed to determine whether decreased thymic output, as well as increased T cell turnover, occur in HIV infection. In individuals experiencing a rebound of viral replication after interruption of therapy, the rapid fall we observed in TREC levels clearly reflects the increase in T cell proliferation. Although not impossible, it is unlikely that the fall in TREC reflects a marked decrease in thymic output, as it has recently been shown that TREC levels only begin to decrease 3 mo after total thymectomy in HIV-uninfected individuals (41).
Therefore, we reasoned that if HIV infection suppressed thymic output, we would be able to detect this effect at least 3 mo after infection. Indeed, our results from the analysis of individuals with early HIV infection 3–12 mo after seroconversion suggest that decreased thymic output begins to affect T cell homeostasis by this stage of the disease. TREC levels were decreased in both CD4+ and CD8+ T cell subsets, and were also significantly decreased when the CD45RO-CD27high (naive) T cell TREC were calculated. As both CD45RO+ (memory) and CD45RO-CD27high (naive) CD8+ T cell populations had higher Ki67 expression in HIV-infected individuals, it was not possible to distinguish between the effects of increased proliferation and reduced thymic output for CD8+ T cells. However, the percentage of Ki67+CD4+CD45RO-CD27high (naive) T cells did not increase. The finding that TREC within naive CD4+ T cells were significantly lower in infected individuals in the context of unaltered naive CD4+ T cell proliferation suggests that the input of TREC+ naive CD4+ T cells into the peripheral naive T cell pool from a "source" has decreased. The thymus is the most likely source for such cells (50).
However, some studies have found that the percentage of Ki67+CD4+ naive T cells increased in HIV-infected individuals (1, 31). The discrepancy between our data and these studies could be due a number of reasons; for example, our subjects had a higher mean CD4 counts, and some Ki67+ cells might be nondividing (3, 43). However, as we have shown, it is more likely that the incorporation of transitional T cells, cells that were naive and have now become activated, into the phenotypically defined naive T cell subset accounts for the apparent increase in CD4+ naive T cell activation and/or proliferation in such studies.
Thus, our data show that by 3 mo after HIV infection, a decrease in TREC within CD45RO-CD27high (naive) CD4+ T cells is clearly detectable in the absence of an increase in CD45RO-CD27high (naive) CD4+ T cell proliferation, which suggests a decrease in thymic output. It is possible that the decrease in TREC could be due to members of the naive pool entering cell cycle, losing TREC due to dilution, and then reverting to a naive phenotype. However, there is no evidence in humans for activated or memory CD4+ T cells reverting to a CD45RO-CD27high phenotype. The effect of HIV on thymic function was further confirmed with the observation that in those individuals with low TREC, CD45RO-CD27high (naive) CD4+ T cell TREC increased with suppression of virus on HAART. This suggests that the thymus can recover from its suppression during HIV infection. It is important to note that an increase in naive T cell TREC can only occur in the context of active thymic output. Therefore, even if decreases in CD4+ T cell TREC occurred due to proliferation and the thymus remained unaffected by HIV, the increase in naive T cell TREC during HAART indicates that the thymus contributes to immune reconstitution. An appreciation of the relative roles of the thymus and peripheral T cell pool in immune reconstitution in HIV infection may provide a framework for the rational design of interventions that accelerate and improve the nature of T cell reconstitution in HIV-infected individuals.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Daniel C. Douek, Vaccine Research Center, Room 3509, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892; E-mail address: ddouek{at}mail.nih.gov
3 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; BrdU, bromodeoxyuridine; TREC, TCR rearrangement excision circles.
Received for publication June 5, 2001. Accepted for publication September 24, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. O. Schonland, J. K. Zimmer, C. M. Lopez-Benitez, T. Widmann, K. D. Ramin, J. J. Goronzy, and C. M. Weyand Homeostatic control of T-cell generation in neonates Blood, August 15, 2003; 102(4): 1428 - 1434. [Abstract] [Full Text] [PDF]
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A. Shen, M. C. Zink, J. L. Mankowski, K. Chadwick, J. B. Margolick, L. M. Carruth, M. Li, J. E. Clements, and R. F. Siliciano Resting CD4+ T Lymphocytes but Not Thymocytes Provide a Latent Viral Reservoir in a Simian Immunodeficiency Virus-Macaca nemestrina Model of Human Immunodeficiency Virus Type 1-Infected Patients on Highly Active Antiretroviral Therapy J. Virol., April 15, 2003; 77(8): 4938 - 4949. [Abstract] [Full Text] [PDF]
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T. Pham, M. Belzer, J. A. Church, C. Kitchen, C. M. Wilson, S. D. Douglas, Y. Geng, M. Silva, R. M. Mitchell, and P. Krogstad Assessment of Thymic Activity in Human Immunodeficiency Virus-Negative and -Positive Adolescents by Real-Time PCR Quantitation of T-Cell Receptor Rearrangement Excision Circles Clin. Vaccine Immunol., March 1, 2003; 10(2): 323 - 328. [Abstract] [Full Text] [PDF]
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R. M. Ribeiro, H. Mohri, D. D. Ho, and A. S. Perelson In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted? PNAS, November 26, 2002; 99(24): 15572 - 15577. [Abstract] [Full Text] [PDF]
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S. R. Lewin, R. M. Ribeiro, G. R. Kaufmann, D. Smith, J. Zaunders, M. Law, A. Solomon, P. U. Cameron, D. Cooper, and A. S. Perelson Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection J. Immunol., October 15, 2002; 169(8): 4657 - 4666. [Abstract] [Full Text] [PDF]
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D. L. Sodora, J. M. Milush, F. Ware, A. Wozniakowski, L. Montgomery, H. M. McClure, A. A. Lackner, M. Marthas, V. Hirsch, R. P. Johnson, 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., August 28, 2002; 76(19): 9981 - 9990. [Abstract] [Full Text] [PDF]
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R. Terra, N. Labrecque, and C. Perreault Thymic and Extrathymic T Cell Development Pathways Follow Different Rules J. Immunol., July 15, 2002; 169(2): 684 - 692. [Abstract] [Full Text] [PDF]
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P. Ye and D. E. Kirschner Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants J. Immunol., May 15, 2002; 168(10): 4968 - 4979. [Abstract] [Full Text] [PDF]
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) and untreated individuals with early (3–12 mo after
seroconversion) HIV infection (•) are shown. Best-fit exponential
regression curves for uninfected individuals are shown.
