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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Clinical Science

CXCR4 Overexpression During the Course of HIV-1 Infection Correlates With the Emergence of X4 Strains

Lin, Yea-Lih PhD*; Portales, Pierre PharmD†; Segondy, Michel PharmD‡; Baillat, Vincent MD§; de Boever, Corinne Merle MD§; Moing, Vincent Le MD§; Réant, Brigitte*†; Montes, Brigitte MD‡; Clot, Jacques MD†; Reynes, Jacques MD§; Corbeau, Pierre MD, PhD*†

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From the *Institut de Génétique Humaine, †Laboratoire d'Immunologie, and ‡Laboratoire de Virologie, Hôpital Saint Eloi, and §Service des Maladies Infectieuses et Tropicales, Hôpital Gui de Chauliac, Montpellier, France.

Received for publication October 5, 2004; accepted May 25, 2005.

Supported by the Agence Nationale de Recherche sur le SIDA (ANRS). Y-LL was supported by a fellowship from SIDACTION.

Reprints: Pierre Corbeau, Laboratoire d'Immunologie, Hopital Saint Eloi, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France (e-mail: pierre.corbeau@igh.cnrs.fr).

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Abstract

The factors that determine the emergence of X4 isolates in some HIV-1-infected subjects are unknown. As the level of expression of CXCR4 could favor an R5 to X4 switch, quantitative flow cytometry was used to measure CXCR4 density on CD4+ T cells in 200 HIV-1-positive adults, and this was compared with CD4 counts, interleukin-7 (IL-7), and RANTES (regulated on activation, normal T expressed and secreted) plasma levels and the R5/X4 virus phenotype. CD4+ T-cell surface CXCR4 densities were increased in infected subjects and inversely correlated with CD4+ T-cell count (r = −0.548, P < 0.001). Yet, in vitro infection with either R5 or X4 strains and in vivo increases in viral load following interruption of antiretroviral treatment did not induce CXCR4 overexpression. The plasma levels of IL-7 and RANTES, 2 cytokines able to induce CXCR4 expression, did not correlate with CXCR4 density. Finally, higher CXCR4 densities were observed in patients harboring X4 strains (3300, 95% CI 2431-4169 CXCR4 molecules per cell) than in patients harboring only R5 strains (2406, 95% CI 2135-2677, P = 0.027). These data suggest that CXCR4 overexpression during the course of the disease in some patients could favor the emergence of X4 strains.

The chemokine receptors CCR5 and CXCR4 are the main coreceptors used by the R5 and X4 HIV-1 strains, in addition to the CD4 receptor.1 Whereas R5 viruses can be detected at all stages of infection, X4 strains are only isolated from one-half to one-third of patients with late-stage disease.2 The reasons for the emergence of X4 strains in some patients but not in others are unknown. As this emergence has been correlated with rapid disease progression,3 it is important to identify the factors responsible for the R5 to X4 switch.

We have previously shown that the mean number of CCR5 molecules per CD4+ peripheral blood T lymphocyte is constant over time for a given individual, whether the person is infected with HIV-1 or not.4 Yet, the CD4+ T-cell surface CCR5 density varies among individuals and is strongly correlated in HIV-infected persons with viral load4 and disease progression.5 Interestingly, this correlation is logarithmic; a moderate difference in CCR5 density corresponds to a marked difference in HIV-1 RNA plasma level. We have demonstrated that CCR5 cell surface density determines the intensity of virus production in vitro.6 Of note, this effect is exerted at a postentry level, mainly on the efficiency of reverse transcription. Here again, the correlation between CCR5 expression and HIV production is logarithmic, a 7-fold difference in cell surface CCR5 density resulting in a 30- to 80-fold difference in virus production after a single virus life cycle. Taken together, these data show that the level of expression of the CCR5 coreceptor on CD4+ T cells strongly determines their infectability.

By analogy, we hypothesized that CXCR4 expression could be involved in the development of X4 strains. To test this hypothesis, CXCR4 density on the peripheral blood T cells of HIV-infected subjects was analyzed during the course of the disease.

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METHODS

Study Subjects

Two hundred adults (72 women and 128 men, mean age of 39 years; range 18-72 years) infected by HIV-1 for >6 months and age-matched healthy volunteers were recruited at the University Hospital of Montpellier. Their CD4 cell counts ranged from 7-1407 (arithmetic means of 373, 95% CI 333-413). Their HIV RNA plasma level, determined by a commercial assay (Amplicor HIV-1 Monitor, version 1.5; Roche Diagnostic Systems), ranged from <20-980,000 copies/mL (arithmetic means of 96,439, 95% CI 65,939-126,940). They were asymptomatic or not, and some were treatment naive, but others were or had been under treatment. Among the 48% who were under therapy, 11% received nucleoside analogues only, 27% nucleoside analogues and protease inhibitors, 8% nucleoside and nonnucleoside reverse transcriptase inhibitors, and 2% nucleoside and nonnucleoside reverse transcriptase inhibitors with protease inhibitors. Blood was collected at distance (6 months) of any introduction, change, or interruption of therapy. The study was approved by the local ethics committee.

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CXCR4 Phenotyping

CD4+ T-cell surface CXCR4 densities were determined by quantitative flow cytometry as described elsewhere.4 For this purpose, blood was collected in ethylenediamine tetra-acetic acid tubes. Within 2 hours after the blood was drawn, cells were directly labeled with a phycoerythrin-conjugated anti-CD4 monoclonal antibody (MAb) and indirectly labeled with an anti-CXCR4 (12G5) MAb (Pharmingen, San Jose, CA) and a fluorescein isothiocyanate-conjugated anti-immunoglobulin probe (H+L; Jackson ImmunoResearch Laboratories, West Grove, PA). After gating on CD4+ T cells, the intensity of CXCR4 expression on CXCR4+ cells was analyzed by converting fluorescein isothiocyanate fluorescence into the mean number of cell surface-bound MAb molecules per cell, using populations of standard microbeads precoated with different well-defined quantities of MAb (QIFIKIT; Dako, Glostrup, Denmark) and concurrently labeled with the same fluorescein isothiocyanate-conjugated anti-immunoglobulin probe.

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HIV Infection Assay

Peripheral blood mononuclear cells were isolated by Ficoll-Hypaque density gradient centrifugation, stimulated for 24 hours with phytohemagglutinin P (3 μg/mL, Difco Laboratories, Le Pont de Claix, France), exposed to 8 ng of p24 equivalent of an HIV-1 strain for 24 hours, washed extensively, and cultured at 2 × 106 cells/mL in 0.5 mL of RPMI1640 (Roswell Park Memorial Institute) (Gibco) supplemented with 10% fetal calf serum, antibiotics, glutamine, and 100 U/mL of interleukin-2 (Boehringer-Mannheim, Indianapolis, IN). Control cultures were performed without infection. At days 0 (ie, before infection), 3, 7, 10, and 14, aliquots of cells were quantitatively phenotyped for CXCR4 expression as described here. Cell surface receptor density was calculated as previously described4: {1 − [(A − B)/A]} × 100, where A represents the receptor density on noninfected cells and B the receptor density on infected cells. HIV-1 p24 concentration was determined in the culture supernatants by using a commercial enzyme-linked immunosorbent assay kit (Coulter).

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Cytokine Determinations

Plasma specimens stored at −70°C were thawed, filtered (0.2 μm), and analyzed for interleukin-7 (IL-7) and RANTES (regulated on activation, normal T expressed and secreted) concentrations using commercial immunoassays (R&D Systems).

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Virus Phenotyping

X4 phenotype was determined using the MT2 assay.7 Briefly, patient peripheral blood mononuclear cells were depleted in CD8+ T cells using anti-CD8 antibody-coated magnetic beads (Dynal Biotech, Cape Town, South Africa) and cocultured with phytohemagglutinin-stimulated donor peripheral blood mononuclear cells. CD4+CCR5CXCR4+ MT2 cells cultivated at 106 cells/mL were inoculated with 500 μL of coculture supernatant containing >400 pg/mL of HIV-1 p24 gag antigen and monitored over 14 days for the presence of syncytia.

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Statistical Analysis

CXCR4 expression on CD4+ T cells from infected and noninfected individuals, and from R5 and X4 strain-harboring patients, was compared by the Mann-Whitney U test. Cytokine plasma concentrations in R5+ and X4+ patients were compared with the same test. Spearman rank correlations were used as a measure of association between CXCR4 expression, CD4 cell count, viremia, or cytokine level in plasma.

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RESULTS

CXCR4 Is Overexpressed in HIV-1-Infected Persons

We analyzed CXCR4 expression on peripheral CD4+ T cells of 160 healthy volunteers and 200 HIV-infected patients at various stages of the disease. In addition to the percentage of CD4+ T cells expressing CXCR4, we also determined the mean number of CXCR4 molecules at the surface of each CD4+ T cell by using a quantitative flow cytometry assay. In this assay, the mean fluorescence intensity is converted to CXCR4 density by calibration with a standard curve obtained with microbeads coated with well-defined quantities of antibodies (as described in “Methods”). Figure 1A shows that CXCR4 density on CD4+ T cells was higher in HIV-infected than in noninfected subjects (arithmetic means of 2301, 95% CI 2139-2463; and 1721, 95% CI 1603-1839 CXCR4 molecules per cell, respectively, P < 0.001). Likewise, the percentage of CD4+ T cells expressing CXCR4 was higher in HIV-infected than in noninfected subjects (arithmetic means of 31%, 95% CI 28-34; and 20%, 95% CI 17-23, respectively, P < 0.001). An example of CXCR4 expression in a healthy volunteer and in an HIV-infected high-CXCR4 expressor is shown in Figure 1B and C.

Figure 1
Figure 1
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CXCR4 Expression Is Not Linked to HIV Production

One hypothesis that could account for the CXCR4 overexpression we observed in HIV-positive subjects is that HIV infection per se could induce CXCR4. We tested this hypothesis in vitro and in vivo.

First, we monitored CXCR4 density at the surface of peripheral blood mononuclear cells, isolated from a healthy volunteer, after in vitro infection with the R5 isolate Ada-M or the X4 strain NL4-3. Neither infection with Ada-M nor with NL4-3 was associated with the induction of CXCR4 at the surface of the infected mononuclear cells (Fig. 2A and B).

Figure 2
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We also analyzed the effects of HIV production on CXCR4 expression in vivo. For this purpose, we systematically recruited 8 patients for whom treatment interruption had been decided and followed CXCR4 density at the surface of their CD4+ T cells. One month after interruption of treatment, viral load increased (645, 95% CI 0-1592; and 166,599, 95% CI 0-391,857) copies/mL before and after interruption, respectively, P = 0.008; Fig. 2C), CD4 count decreased (693, 95% CI 311-1075; and 462, 95% CI 171-752 copies/mL before and after interruption, respectively, P = 0.031; data not shown), but CD4+ T-cell CXCR4 density remained constant (1789, 95% CI 1425-2154; and 1627, 95% CI 1326-1928 molecules/cell before and after interruption, respectively, P = 0.734; Fig. 2C). Of note, at least one of these patients (open triangles) harbored X4 strains.

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CD4+ T-cell CXCR4 Density Inversely Correlates With CD4 Cell Count

Next, we assessed whether there was a link between CXCR4 density and HIV disease stage. Figure 3 shows a strong correlation between CD4+ T-cell surface CXCR4 density and CD4 cell count (r = −0.548, P < 0.001). Overall, CXCR4 expression increased logarithmically during the course of the disease. At >400 CD4+ T cells/mL, the CXCR4 densities were normal, but at <400 CD4+ T cells/mL, and particularly at <200 CD4+ T cells/mL, there was a sharp rise in CXCR4 density. Yet, even at <200 CD4+ T cells/mL, about two-thirds of the patients had a normal CXCR4 density. Similarly, the percentage of CD4+ T cells expressing CXCR4 correlated with the CD4 cell count, albeit less strongly (r = −0.156, P = 0.047). In addition, CXCR4 density on the CD4+ T cells correlated with viral load (r = 0.329, P < 0.001).

Figure 3
Figure 3
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CXCR4 Density on CD4+ T Cells Does Not Correlate With IL-7 or RANTES Plasma Levels

To study factors associated with CXCR4 overexpression in the late stages of HIV-1 infection, we screened for factors reported to induce CXCR4 expression and to be increased during the course of the disease. One of these factors is IL-7, which has been shown to induce CXCR4 expression on peripheral blood mononuclear cells8,9 and to be increased in patients with low CD4+ T-cell counts.10 Therefore, we measured IL-7 in the plasma of the patients whose CD4+ T-cell surface CXCR4 density was determined. Figure 4A shows that plasma IL-7 levels were inversely correlated with CD4+ T-cell counts (r = −0.445, P < 0.001), as previously reported.9,10 Yet, IL-7 plasma concentration did not correlate with CD4+ T-cell surface CXCR4 density (r = 0.011, P = 0.938; Fig. 4B).

Figure 4
Figure 4
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Likewise, the C-C chemokine RANTES has been shown to induce CXCR4 expression11 and to be overproduced during the late stages of HIV disease.12 Thus, we measured RANTES in plasma of the patients whose CD4+ T-cell surface CXCR4 density was determined. Figure 4C and D show that the plasma levels of RANTES did not correlate with either the CD4 cell count (r = 0.108, P = 0.584) or the CD4+ T-cell surface CXCR4 density (r = −0.195, P = 0.320).

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Patients Harboring X4 Strains Overexpress CXCR4

To test the hypothesis that the CD4+ T-cell surface CXCR4 overexpression we observed in some patients might have favored the emergence of CXCR4-using HIV-1 strains, we compared the CXCR4 densities on T cells of patients in whom X4 strains had or had not been isolated. For this purpose we systematically recruited 72 patients with <400 CD4+ T cells/μL, measured their CXCR4 expression, and characterized the phenotype of the strains they harbored. In this cohort, the percentage of men (77 and 80, P = 0.850), the age (44 years, 95% CI 40-48 years; and 40 years, 95% CI 35-45 years, P = 0.331), the CD4 counts (189, 95% CI 162-217; and 179, 95% CI 133-226 CD4+ T cells/μL; P = 0.777), the viral load (187,000, 95% CI 102,000-273,000; and 142,000, 95% CI 27,000-257,000 copies/mL; P = 0.502), and the percentage of treated patients (29% and 29%, P = 0.982) were similar. Figure 5 shows that the 24 patients infected with X4 strains expressed higher CXCR4 densities than 48 patients who did not (3298, 95% CI 2579-4017; and 2516, 95% CI 2238-2794 CXCR4 molecules per cell, respectively, P = 0.021). We found no difference in the plasma concentrations of IL-7 (13, 95% CI 8-18; and 16, 95% CI 12-20 ng/mL, respectively, P = 0.211) and RANTES (36, 95% CI 19-53; and 47, 95% CI 30-64 ng/mL, respectively, P = 0.346) between the 2 groups of patients.

Figure 5
Figure 5
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DISCUSSION

In the present study, we show that the mean number of CXCR4 molecules at the surface of CD4+ T cells is increased in one-third of late-stage HIV-1-infected subjects and that this overexpression is linked to the presence of X4 strains, as determined by the MT2 assay. It is important to note the limitations of this classic assay, in terms of sensitivity and because it is based on virus derived from stimulated lymphocytes rather than directly from plasma, by contrast with more recent recombinant phenotypic assays.13

As we previously demonstrated for CCR5,4,5 we observed a physiological interindividual variability in CD4+ T-cell surface CXCR4 density, which ranged from 699-4808 molecules per cell in healthy volunteers. Interestingly, although the proportion of CD4+ T cells expressing CXCR4 was found to be higher than the proportion of CD4+ T cells expressing CCR5, the mean CD4+ T-cell surface CXCR4 density was lower than the mean CD4+ T-cell surface CCR5 density. These results are in agreement with a previous report.14 If CXCR4 cell surface density modulates X4 infectability in the same manner that CCR5 cell surface density modulates R5 infectability,6 the physiological low CD4+ T-cell surface CXCR4 density might explain why a CXCR4+ T cell produces less virus than a CCR5+ T cell, as proposed by Michael and Moore.2 Moreover, it may be hypothesized that the low physiological CD4+ T-cell surface CXCR4 density initially limits X4 strain spread, which could be favored by an increase in the level of CXCR4 expression.

The reasons for the CXCR4 overexpression we observed in some patients with late-stage disease remain unclear.

Various elements argue against a direct role of infection per se. First, we observed no increase in CD4+ T-cell surface CXCR4 density during the course of R5 or X4 in vitro infection, as reported by others.15 CXCR4 has even been shown to be downregulated in cells infected with an X4 strain, m7NDK.16 Second, CD4+ T-cell surface CXCR4 density remained stable in patients whose retroviral multitherapy was interrupted, despite a drastic increase in their viremia. Finally, in vivo, it might be expected that X4 infection would counterselect against CD4+ T cells expressing high CXCR4 densities rather than induce the emergence of such cells.

We tested whether IL-7 was associated with CXCR4 overexpression during the course of HIV infection. Llano et al9 reported a higher IL-7 plasma concentration in patients with syncytia-inducing strains than in patients with non-syncytia-inducing strains; they proposed that IL-7 might be involved in the emergence of syncytia-inducing strains of HIV-1. This model is attractive: during the course of HIV-induced T-cell depletion, IL-7 production could increase in an attempt to stimulate lymphocyte development and expansion.10 As a side effect, IL-7 overproduction would then induce CXCR4 overexpression at the CD4+ T-cell surface. Yet, this hypothesis does not take into account the fact that CXCR4 overexpression occurs in only a minority of patients, whereas T-cell depletion occurs in all patients. Moreover, we did not find any correlation between IL-7 plasma levels and CXCR4 expression, and there was no difference in IL-7 plasma levels between X4+ and R5+ patients.

We also questioned whether RANTES was associated with CXCR4 overexpression. RANTES is a good candidate, because this chemokine has been reported to induce CXCR4 expression and thereby to increase X4 strain adsorption and replication11 and to be overexpressed as the disease progresses.12 Yet, we did not find a correlation between RANTES plasma levels and either CD4 cell counts or CXCR4 expression. Moreover, X4+ patients did not have higher RANTES plasma concentrations than R5+ patients. Yet, it must be emphasized that the present study is cross-sectional, so that the effects of IL-7 or RANTES on CXCR4 expression may have been overlooked. For instance, these cytokines might actually induce a CXCR4 overexpression that boosts X4 proliferation, resulting in the death of the very cells that overexpress CXCR4. Thus, the cause of the CXCR4 overexpression we detected in patients with late-stage disease remains to be unveiled. In particular, it will be important to determine whether CXCR4 overexpression at the cell surface is the consequence of an overproduction of the chemokine receptor by CD4+ T cells or rather a consequence of the redistribution of the chemokine receptor between the inside and the outside of the cell. Alternatively, the CXCR4 overexpression we observed at the surface of peripheral blood CD4+ T cells might be the consequence of changes in lymphocyte subpopulations in favor of T cells overexpressing CXCR4. For instance, CD4+ T-cell surface CXCR4 density has been shown to be higher on naive cells than on memory cells,14 and CD4+ memory T cells are known to be selectively depleted during the course of the infection.17 Likewise, CXCR4 surface density is 4-fold higher in TH2 vs. TH1 subpopulations,18 and some data argue for an increase in the proportion of TH2 cells over time in infected subjects.19 Moreover, antigen stimulation increases CXCR4 expression at the surface of CD4+ T cells,20 and the percentage of activated T cells rises as the disease progresses.

The pattern of CXCR4 overexpression is strikingly similar, in terms of timing and frequency, to the emergence of X4 strains. We observed an increase in CXCR4 density to <400 CD4+ T cells/μL and, in particular, at levels <200 CD4+ T cells/μL, a stage at which X4 strains preferentially develop.7,21,22 We also observed CXCR4 overexpression at this advanced stage in only about one-third of the patients, a proportion comparable to the percentage of patients who harbor X4 strains. Moreover, we found that CXCR4 overexpression was linked to the R5 to X4 switch. The question is now what is the causality of this correlation? As discussed previously, there is no argument in favor of the hypothesis that the development of X4 strains induces CXCR4 expression. Rather, it can be hypothesized that secondary to an event occurring in one-third of the patients with <400 CD4+ T cells/μL, CXCR4 density could increase at the CD4+ T-cell surface, and that this increase, in the same way as the high CCR5 density at the CD4+ T-cell surface induces high R5 production,6 and consistent with previous studies linking CXCR4 expression with X4 infectability,18,23 could facilitate the development of X4 strains that were previously hindered by the relatively low CD4+ T-cell surface CXCR4 density.

If this hypothesis proves to be correct, then the CXCR4 density could be a parameter of predictive value regarding the risk of an R5 to X4 switch, and CXCR4 antagonists administered to patients overexpressing CXCR4 might prevent such a switch. Moreover, on the basis of this hypothesis, the identification of the factor(s) responsible for the increase in CXCR4 density might allow an efficient prevention of this deleterious event.

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ACKNOWLEDGMENTS

We are indebted to N. Taylor for critical reading of the manuscript and to S. L. Salhi for its editing.

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5. Reynes J, Portales P, Segondy M, et al. CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. AIDS. 2001;15:1627-1634.

6. Lin Y-L, Mettling C, Portales P, et al. Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. Proc Natl Acad Sci USA. 2002;99:15590-15595.

7. Koot M, Keet RP, Voos AH, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993;118:681-688.

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9. Llano A, Barretina J, Gutiérrez A, et al. Interleukin-7 in plasma correlates with CD4 T-cell depletion and may be associated with emergence of syncytium-inducing variants in human immunodeficiency virus type 1-positive individuals. J Virol. 2001;75:10319-10325.

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12. Zanussi S, D'Andrea M, Simonelli C, et al. Serum levels of RANTES and MIP-1α in HIV-positive long-term survivors and progressor patients. AIDS. 1996;10:1431-1432.

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14. Lee B, Sharron M, Montaner LJ, et al. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA. 1999;96:5215-5220.

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16. Valente ST, Chanel C, Dumonceaux J, et al. CXCR4 is down-regulated in cells infected with CD4-independent X4 human immunodeficiency virus type 1 isolate m7NDK. J Virol. 2001;75:439-447.

17. van Noesel CJ, Gruters RA, Terpstra FG, et al. Functional and phenotypic evidence for a selective loss of memory T cells in asymptomatic human immunodeficiency virus-infected men. J Clin Invest. 1990;86:293-299.

18. Moonis M, Lee B, Bailer RT, et al. CCR5 and CXCR4 expression correlated with X4 and R5 HIV-1 infection yet sustained replication in TH1 and TH2 cells. AIDS Res Hum Retroviruses. 2001;15:1941-1949.

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23. Zaitseva M, Lee S, Rabin RL, et al. CXCR4 and CCR5 on human thymocytes: biological function and role in HIV-1 infection. J Immunol. 1998;161:3103-3113.

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Keywords:

coreceptor; chemokine; R5 to X4 switch; CD4+ T cell; virus phenotype

© 2005 Lippincott Williams & Wilkins, Inc.

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