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*
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Division of Infectious Diseases, Georgetown University, Washington, DC 20057
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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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-chemokine
receptor, CXCR4, is most likely also of importance since usage of CXCR4
by HIV-1 isolates often evolves during disease progression associated
with the emergence of syncytium-inducing
(SI)2 variants (11, 12, 13, 14).
Recent studies have (15, 16) demonstrated a relatively reciprocal
relationship between CCR5 and CXCR4 expression on PBMCs taken from
normal individuals. CXCR4 was expressed predominantly on
CD26low, CD45RA+, CD45RO- T cells,
indicating a naive unactivated phenotype; and CCR5 was expressed on
CD26high, CD45RA-, CD45RO+,
CD25-, CD69-, CD95+ T cells, a
phenotype consistent with previously activated memory cells.
Cellular activation is critical for productive infection in vitro and
in vivo (17, 18, 19, 20). Thus, it can be postulated that the major targets for
initial infection by HIV-1 are those CD4+ T cells that
express an appropriate coreceptor and are activated, i.e.,
CCR5-expressing memory cells. In addition, HIV-1-infected individuals
manifest persistent CD4+ and CD8+ T cell
activation, which provides an optimal environment for continuous viral
replication (21, 22, 23, 24). In the present study, we have examined the expression of CCR5 and CXCR4 on fresh whole blood samples taken from HIV-1-infected and uninfected individuals. In addition, we had the opportunity to temporally follow HIV-1 coreceptor expression in one individual who was experiencing acute, symptomatic HIV-1 seroconversion. We compared CXCR4 and CCR5 expression in the context of cellular activation markers and stage of disease. Our findings indicate that the heightened state of cellular activation in HIV-1-infected individuals is associated with CCR5 up-regulation and CXCR4 down-regulation on CD4+ T cells, and that this milieu may favor the propagation of macrophage-tropic (CCR5-using) viruses. In those patients with SI viruses, we could not find significant differences in the levels of cellular activation, nor expression of CXCR4 and CCR5 on CD4+ T cells in comparison with those patients harboring only nonsyncytium-inducing (NSI) viruses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A mAb to CXCR4 (12G5) was a generous gift from Dr. James
Hoxie (25). A mAb to CCR5 (5C7) was kindly provided by Dr.
Charles MacKay (16). All of the following (FITC, phycoerythrin
(PE), PerCP) conjugated mAbs were obtained from Becton Dickinson (San
Jose, CA): anti-mouse IgG1, and IgG2a isotype controls,
anti-CD45, anti-CD14, anti-CD4, anti-CD8,
anti-HLA-DR, and anti-CD3. An unconjugated mouse polyclonal
isotype IgG was obtained from Sigma (St. Louis, MO). A goat
anti-mouse F(ab')2 light and 
-chain human
Ig-adsorbed FITC was obtained from Biosource (Camarillo, CA).
Patients and control subjects
Twenty-five HIV-1-infected adults and ten control volunteers were recruited from the Washington D.C. area. Fifty-two percent of the HIV-1-infected subjects were receiving highly active antiretroviral treatment that included a protease inhibitor. Most patients were asymptomatic. Patient 22 presented with an acute seroconversion illness; he is a 47-yr-old homosexual male who presented with fever, rash, pharyngitis, severe malaise, and diarrhea 2 wk after a high risk exposure. Patient 3 is a recent asymptomatic seroconverter (HIV-infected <1 yr). Patient 23 is being treated for chronic bacterial sinusitis.
Blood was drawn by venipuncture from each subject in EDTA tubes (Becton Dickinson) for FACS analysis, CBC, plasma viral load, and absolute CD4+ T cell count. All samples for FACS analysis were prepared within 2 h of the draw.
Whole blood surface staining and FACS analysis
For cytofluorometric analyses in this study, we used the following Ab combinations: 1) CD45 (FITC) and CD14 (PE); 2) CD4 (FITC) and CD8 (PE); 3) CD4 (FITC) or CD8 (FITC) and HLA-DR (PE) and CD3 (PerCP); 4) 12G5 or 5C7 (FITC) and CD4 (PE) and CD3 (PerCP), 5) 12G5 or 5C7 (FITC) and CD8 (PE) and CD3 (PerCP); 6) 12G5 or 5C7 (FITC) and CD14 (PE); and 7) 12G5 or 5C7 (FITC) and HLA-DR (PE) and CD4 (PerCP).
For each stain, 100 µl of whole blood was washed in PBS/1% FCS/0.02% sodium azide. For unconjugated Abs, blood was incubated with either unconjugated isotype, 12G5, or 5C7 for 30 min on ice at final concentrations of 1, 8, and 5 µg/ml, respectively. Blood was washed and then incubated with a 1/50 dilution of a FITC goat anti-mouse Ig F(ab')2 for 15 min. Blood was washed again, and finally, the appropriate directly conjugated mAb(s) was added. The blood was washed, RBCs were lysed, and cells were fixed and suspended in 1% paraformaldehyde in PBS. Three-color flow-cytometric analysis was performed on a dual-laser Epics-C Coulter flow cytometer (Hialeah, FL). At least 5000 events were counted for each stain. For subset analysis, lymphocyte or monocyte gates as well as gates uniquely identifying CD3 or CD14 cells were applied. For example, CXCR4 expression of CD4+ T cells was obtained after gating for lymphocytes based on forward and side scatter, and then gating on CD3+ positive cells.
Plasma viremia quantitation
Plasma viremia was quantitated using branched DNA methodology (Chiron, Emeryville, Ca). All plasma viremia quantitations from patient 22 were obtained using quantitative reverse-transcriptase PCR (J. Lifson et al., unpublished data).
Virus isolation and phenotyping
PBMCs from HIV-infected patients were depleted of CD8+ T cells by magnetic beads (Dynal, Oslo, Norway) and cultured in complete medium (RPMI 1640, 2% penicillin-streptomycin, 2% L-glutamine; BioWhittaker, Walkersville, MD) in the presence of heat-inactivated 10% FCS at 37°C, irradiated feeder cells (HIV-uninfected blood donor), anti-CD3 Ab (mouse ascites, 1/4000 dilution), and IL-2 (20 U/ml; Boehringer Mannheim, Mannheim, Germany) at 37°C in a 5% C02 atmosphere. Three-day-old CD8--depleted, anti-CD3 Ab-stimulated blasts from HIV-negative donors were added to the cultures on the following day and 1 wk later. Reverse-transcriptase activity was monitored at day 14 and was performed as previously described (17). Cultured virus was phenotyped using an MT2 cell assay. A total of 50 µl of culture supernatant was added to 0.1 x 106 MT2 cells (National Institutes of Health AIDS Research and Reference Reagent Program) in 96-well plates. The assay was performed in quadruplicate, and was monitored for the presence of syncytia over a 2-wk period.
CCR5 genotype analysis
CCR5 genotype was determined according to previously described methods (9).
Statistical analysis
Geometric means were determined for log-normally distributed variables. Means are reported with 1 SE. Comparisons of means were done using analysis of variance; for log-normally distributed residuals, data were logged for analysis. Comparison of CXCR4 expression in CD14+ monocytes that had skewed distributions was done using the Wilcoxon 2-sample test, and the medians are reported. Spearman rank correlations were used as a measure of association between percentage of CD4 and other variables. HLA-DR expression of CXCR4+CD4+ T cells and CCR5+CD4+ T cells was compared by the paired t test. The Bonferoni method of adjusting p values for multiple testing was used.
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Results |
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Clinical and laboratory data on 25 HIV-1-infected patients in
various stages of disease and on 10 uninfected control subjects are
summarized in Tables I and II, respectively. FACS analysis of PBMCs
within fresh whole blood specimens was performed. As expected, the
level of cellular activation as measured by HLA-DR expression in both
CD4+ and CD8+ T cells was significantly greater
in HIV-infected patients than in HIV-uninfected control subjects (for
CD4+ T cells, geometric means of 18.5% (95% CI: 14.6,
23.3) and 3.9% (95% CI: 2.9, 5.2), p = 0.03; for
CD8+ T cells, geometric means of 39.3% (95% CI: 33.6, 46)
and 8.9% (95% CI: 5.9, 13.6), p < 0.001,
HIV-infected and HIV-uninfected individuals, respectively) (Fig. 1
). CXCR4 expression in both
CD4+ and CD8+ T cells and CD14+
monocytes was reduced significantly when compared with HIV-uninfected
controls (Fig. 2) (for CD4+ T
cells, arithmetic means of 22.8% (95% CI: 18, 27.6) and 64% (95%
CI: 52.9, 75.2), p = 0.03; for CD8+ T
cells, geometric means of 10.7% (95% CI: 7.5, 15.3) and 61.1% (95%
CI: 51.6, 72.4), p < 0.001; for monocytes, medians 8.9
and 68.5%, p < 0.001, for HIV-infected and
HIV-uninfected individuals, respectively). Conversely, CCR5 expression
on CD4+ T cells of HIV-infected individuals was increased
significantly when compared with HIV-uninfected controls (Fig. 3) (arithmetic means of 13.2% (95% CI:
10.3, 16.1) expression vs 6.5% (95% CI: 4.1, 8.9), p
= 0.03, in HIV-infected and HIV-uninfected individuals, respectively).
However, CCR5 expression of CD8+ T cells was not
significantly different between the HIV-infected and HIV-uninfected
groups (arithmetic means of 28.2% (95% CI: 22.1, 34.2) vs 21.2%
(95% CI: 12.7, 29.9), p > 0.5, respectively). CCR5
expression on monocytes was undetectable to low (<5%) in both study
groups (data not shown). Of note was the large degree of
interindividual variability of CXCR4 and CCR5 expression on lymphocytes
and monocytes in both populations. The variability in CCR5 expression
within the HIV-infected group could not be explained entirely by CCR5
genotype. For example, CD4+ T cells from patients 14, 16,
and 24, who are heterozygotes for the 32-bp deletion of CCR5
(
32CCR5), showed levels of CCR5 expression of 2.7, 17,
and 13.1%, respectively, which as a group were not significantly
different from the mean level of CCR5 expression among CCR5 wild-type
patients. The one 32CCR5-heterozygous HIV-uninfected
control subject, however, did demonstrate the lowest levels of CCR5
expression of the control group, i.e., 1.7% of CD4+ T
cells, and 0.7% of CD8+ T cells. The level of CXCR4 and
CCR5 expression was stable for asymptomatic individuals who were
sampled repeatedly and were followed over a 1-mo period (data not
shown). A typical example of coreceptor expression in an uninfected
individual is shown in Figure 4A. The most dramatic changes
in coreceptor expression in vivo were observed in patient 22, who
presented with an acute seroconversion illness (Fig. 4B).
Both CD8+ and CD4+ T cells showed high levels
of activation, as reflected by HLA-DR expression of 84 and 28%,
respectively. These changes were associated with marked down-regulation
of CXCR4 expression in CD8+ and CD4+ T cells
(1.2 and 10%, respectively), and up-regulation of CCR5 (76 and 29%,
respectively). Sampling of this patient over a 5-wk period (Fig. 5) showed a decrease in CCR5 expression
on CD4+ T cells (and CD8+ T cells, data not
shown) that paralleled resolution of symptoms, decrease in plasma
viremia, and return of CD4+ T cell count to a new baseline.
Low levels of CXCR4 expression, however, continued over the study
period.
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We examined the levels of HLA-DR expression on CXCR4- and
CCR5-expressing CD4+ T cells (Fig. 6). Among both HIV-infected and
HIV-uninfected individuals, CXCR4+CD4+ T cells
had significantly lower levels of HLA-DR expression when compared with
CCR5+CD4+ T cells (geometric means of 12.5%
(95% CI: 7.8, 20.1) and 51.1% (95% CI: 42.1, 60.1), respectively,
p < 0.001 for HIV-infected group; geometric means of
4.8% (95% CI: 3.3, 7) and 27.9% (95% CI: 22.8, 32.9), respectively,
p < 0.001 for HIV-uninfected group). A representative
patient (1) is shown in Figure 7, in
which 38% of CCR5+CD4+ T cells also expressed
HLA-DR, whereas only 5% of CXCR4+CD4+ T cells
were also HLA-DR+. In addition, the level of CCR5
expression in the entire group of patients (HIV-infected and
uninfected) positively correlated with the activation state of the
CD4+ T cells, as reflected by HLA-DR expression, whereas
the level of CXCR4 expression negatively correlated with HLA-DR on
CD4+ T cells (data not shown).
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The degree of CD4+ T cell activation as measured by
HLA-DR expression directly correlated with advanced disease
(r = -0.65, p = 0.001) (Fig. 8A). In addition, there was a
significant correlation between disease stage and CXCR4 expression of
CD4+ T cells, with healthier patients expressing more CXCR4
(r = 0.45, p = 0.05) (Fig. 8B). A significant correlation was observed between CCR5
expression of CD4+ T cells and disease stage, with higher
levels expressed on more advanced patients (p =
-0.5, p = 0.02) (Fig. 8C). The degree of
activation of CCR5+CD4+ T cells correlated with
disease stage, with more advanced patients having a greater proportion
of CCR5+, CD4+ T cells expressing HLA-DR
(r = -0.60, p = 0.04) (Fig. 8D). A similar trend of borderline statistical
significance was observed with CXCR4+CD4+ T
cells in which a higher proportion expressed HLA-DR+ in
patients with more advanced disease (r = -0.54,
p = 0.09) (Fig. 8E). In particular, patients
23 and 25 showed 53.5 and 83.2% of CXCR4+CD4+
cells to be activated. However, this amount of activation was not
observed in all late stage patients (for example, patient 24).
Similarly, a correlation between levels of plasma viremia and degree of
down-regulation of CXCR4 and up-regulation of CCR5 was observed in the
untreated patients (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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32CCR5 are resistant
to HIV-1 infection (7, 8, 9, 28, 29, 30), with few exceptions (7, 31, 32).
Thus, usage of CCR5 by HIV-1 appears to be critical for the maintenance
of a successful infection in susceptible individuals. Primary isolates
of HIV-1 that use CXCR4, although rapidly growing in vitro, emerge
later in the course of infection in approximately 50% of infected
individuals (33). The selective forces preventing the emergence of
CXCR4--using viruses early in HIV-1 infection are unknown.
We evaluated the levels of CCR5 and CXCR4 expression in HIV-1-infected
and uninfected individuals to identify trends that may help explain the
predominance of macrophage-tropic over T cell line-tropic viruses,
particularly during the earlier stages of disease. Using three-color
flow cytometry of whole blood specimens, we found that HIV-1-infected
individuals had a significantly greater percentage of CCR5-expressing
CD4+ T cells compared with normal controls, and marked
down-regulation of CXCR4 on their CD4+ and CD8+
T cells, and CD14+ monocytes. These changes were directly
correlated with the activation state of the cell, with
CXCR4+ being expressed predominantly on quiescent
(HLA-DR-) cells and CCR5 being expressed predominantly on
activated (HLA-DR+) cells. We could most dramatically
demonstrate this finding in patient 22, who experienced an acute HIV
syndrome and had both the highest levels of in vivo CCR5 expression
(70–80% of CD8+ T cells, and 30–40% of CD4+
T cells) and lowest levels of CXCR4 expression (10% of
CD4+ T cells, and 0.3–1% of CD8+ T cells) of
the entire group. In addition, the level of activation of
CD4+ T cells, the down-modulation of CXCR4, and the
up-regulation of CCR5 correlated with advancing disease, which further
supports the reciprocal role that CXCR4 and CCR5 play in cellular
activation (15, 16). It is unclear whether the observed changes in coreceptor expression in HIV infection are specific to HIV infection and replication or whether they are purely a secondary consequence of broad immune activation. CXCR4 and CCR5 expression have been shown to be differentially regulated in vitro depending on the activation stimulus (16). PHA was shown to down-modulate CCR5 and up-regulate CXCR4, whereas a more physiologic stimulus, such as prolonged culture in IL-2 with or without anti-CD3 stimulation, was shown to enhance CCR5 and diminish CXCR4 expression (16). We have similarly studied patients with other forms of chronic immune activation, such as asymptomatic chronic hepatitis C virus infection, and have observed up-regulation of CCR5, but normal to increased CXCR4 expression in CD4+ T cells (data not shown). Thus, our finding of decreased CXCR4 expression during acute and chronic HIV infection suggests that these changes may not be a secondary consequence of broad immune activation, but may be relatively specific to HIV infection. Further evaluation of individuals with other diseases will be necessary to fully evaluate the spectrum of chemokine receptor expression related to various forms of acute and chronic activation.
We found the level of coreceptor expression to be stable within
asymptomatic individual HIV-infected and uninfected individuals when
tested over multiple time points over a 2-mo period. However, a wide
range of variability was noted among individuals, even among the three
HIV-infected individuals who were heterozygous for the
32CCR5 allele, as similarly reported by Wu et al. in
HIV-1-uninfected individuals (15). This implies that surface expression
of CCR5 and CXCR4 among individuals is complex and most likely
regulated by multiple factors.
Bleul and others (16) have shown that CXCR4 is expressed predominantly on naive T cells, and CCR5 on previously activated memory cells. The dual expression of CCR5 and HLA-DR in CD4+ T cells of HIV-infected as well as uninfected inidividuals in our study is consistent with CCR5 being expressed on a subpopulation of memory T cells at a later stage of activation (i.e., CD69-, HLA-DR+). Thus, the increase in the state of activation of CD4+ T cells in HIV-infected individuals would enhance the efficiency of virus replication in general, while the increased expression of CCR5 together with little or no CXCR4 expression on this population of activated CD4+ T cells would theoretically favor the replication of macrophage-tropic as opposed to T cell line-tropic virus. In contrast, naive CD4+ T cells express abundant CXCR4, which would theoretically favor entry of T cell line-tropic HIV-1; however, recent studies have demonstrated that the relatively quiescent metabolic state of these cells does not support efficient viral replication (34, 35).
The mechanisms responsible for the emergence of SI (CXCR4-using) viruses during HIV disease are unknown (11, 33). It is possible that the level of CXCR4 and CCR5 expression on activated CD4+ cells may influence coreceptor usage by HIV-1. For example, a failure to down-regulate CXCR4 on activated CD4+ T cells may favor usage of this receptor by HIV. It is noteworthy that in our study the proportion of CXCR4+, CD4+ T cells with an activated phenotype (HLA-DR+) tended to increase in some patients with advanced disease. Thus, the possibility that a significant number of activated cells dually expressing both CXCR4 and CCR5 could favor conditions for a broader range of coreceptor usage by HIV-1. We, however, could not distinguish patients harboring SI viruses from those with only NSI viruses based on the levels of CXCR4, CCR5, or HLA-DR on CD4+ T cells. In this regard, the relatively small number of patients studied may have precluded a sufficient analysis of this question. In addition, longitudinal studies of HIV-infected patients will likely be necessary to definitively show whether changes in coreceptor expression within a given individual during the course of HIV infection correlate with a change in viral phenotype in vivo.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: SI, syncytium-inducing; CI, confidence intervals; NSI, nonsyncytia-inducing; PE, phycoerythrin; PerCP, peridinin chlorophyll protein.
Received for publication October 21, 1997. Accepted for publication May 22, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, MIP-1ß receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955.[Abstract]
32. Lancet 349:1219.[Medline]
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T. Lehner, C. Doyle, Y. Wang, K. Babaahmady, T. Whittall, L. Tao, L. Bergmeier, and C. Kelly Immunogenicity of the Extracellular Domains of C-C Chemokine Receptor 5 and the In Vitro Effects on Simian Immunodeficiency Virus or HIV Infectivity J. Immunol., June 15, 2001; 166(12): 7446 - 7455. [Abstract] [Full Text] [PDF]
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M. Mack, J. Cihak, C. Simonis, B. Luckow, A. E. I. Proudfoot, H. Bruhl, M. Frink, H.-J. Anders, V. Vielhauer, J. Pfirstinger, et al. Expression and Characterization of the Chemokine Receptors CCR2 and CCR5 in Mice J. Immunol., April 1, 2001; 166(7): 4697 - 4704. [Abstract] [Full Text] [PDF]
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 S. Shalekoff and C. T. Tiemessen Duration of Sample Storage Dramatically Alters Expression of the Human Immunodeficiency Virus Coreceptors CXCR4 and CCR5 Clin. Vaccine Immunol., March 1, 2001; 8(2): 432 - 436. [Abstract] [Full Text] [PDF]
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 B. Shieh, Y.-E. Liau, P.-S. Hsieh, Y.-P. Yan, S.-T. Wang, and C. Li Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5 and CXCR4 Int. Immunol., September 1, 2000; 12(9): 1311 - 1318. [Abstract] [Full Text] [PDF]
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H. Blaak, A. B. van't Wout, M. Brouwer, B. Hooibrink, E. Hovenkamp, and H. Schuitemaker In vivo HIV-1 infection of CD45RA+CD4+ T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4+ T cell decline PNAS, February 1, 2000; 97(3): 1269 - 1274. [Abstract] [Full Text] [PDF]
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V. Patella, G. Florio, A. Petraroli, and G. Marone HIV-1 gp120 Induces IL-4 and IL-13 Release from Human Fc{epsilon}RI+ Cells Through Interaction with the VH3 Region of IgE J. Immunol., January 15, 2000; 164(2): 589 - 595. [Abstract] [Full Text] [PDF]
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A.-M. de Roda Husman, H. Blaak, M. Brouwer, and H. Schuitemaker CC Chemokine Receptor 5 Cell-Surface Expression in Relation to CC Chemokine Receptor 5 Genotype and the Clinical Course of HIV-1 Infection J. Immunol., October 15, 1999; 163(8): 4597 - 4603. [Abstract] [Full Text] [PDF]
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S. Fais, C. Lapenta, S. M. Santini, M. Spada, S. Parlato, M. Logozzi, P. Rizza, and F. Belardelli Human Immunodeficiency Virus Type 1 Strains R5 and X4 Induce Different Pathogenic Effects in hu-PBL-SCID Mice, Depending on the State of Activation/Differentiation of Human Target Cells at the Time of Primary Infection J. Virol., August 1, 1999; 73(8): 6453 - 6459. [Abstract] [Full Text]
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