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(American Journal of Pathology. 2000;157:1811-1818.)
© 2000 American Society for Investigative Pathology

Short Communications

Up-Regulation of CCR5 Expression in the Placenta Is Associated with Human Immunodeficiency Virus-1 Vertical Transmission

Homira Behbahani*, Edwina Popek{dagger}, Patricia Garcia{ddagger}, Jan Andersson*, Anna-Lena Spetz*, Alan Landay§, Zareefa Flener and Bruce K. Patterson

From the Department of Medicine,*
Division of Infectious Diseases, Karolinska Institutet Huddinge University Hospital, Stockholm, Sweden; the Department of Pathology,{dagger}
Baylor Collage of Medicine, Houston, Texas; the Department of Obstetrics and Gynecology,{ddagger}
Northwestern University Medical School, Chicago, Illinois; the Department of Immunology/Microbiology,§
Rush Medical College, Chicago, Illinois; and the Department of Pediatrics, Division of Infectious Diseases, Children’s Memorial Hospital/Northwestern University Medical School, Chicago, Illinois


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The role of placenta in vertical transmission is not yet fully understood. A protective role of the placenta during gestation is suggested by the finding that caesarian sections reduce the risk of transmission of human immunodeficiency virus (HIV)-1 from mother to child three- to fourfold. Here we investigated whether the immunological milieu of the placenta might be important in HIV-1 transmission. In situ imaging of immunohistochemically stained placenta sections and reverse transcriptase-polymerase chain reaction demonstrated a fourfold increase in CCR5:CXCR4 expression ratio in placentae from transmitting women compared to placentae from nontransmitting women. This chemokine receptor repertoire was consistent with an up-regulation of interleukin-4 and interleukin-10 expression in placentae from nontransmitting placentae compared to transmitting placentae. In situ imaging demonstrated that CCR5 and CXCR4 were expressed on placental macrophages and lymphocytes but not in trophoblasts. Simultaneous immunofluorescence/ultrasensitive in situ hybridization for HIV-1 gag-pol mRNA revealed that HIV-1 infects primarily CXCR4-expressing cells in placentae from nontransmitting women whereas predominantly CCR5-expressing cells were infected in placentae from transmitting women. These data are consistent with transmission of a homogeneous population of nonsyncytium-inducing HIV-1 isolates that use CCR5 as co-receptor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Vertical transmission of human immunodeficiency virus (HIV)-1 occurs in ~14 to 39% of pregnancies unless antiretroviral treatment is provided.1,2 The neonatal infection rate is reduced to ~8 to 9% if zidovudine (AZT) treatment is implemented throughout the perinatal period.3 Elective caesarian sections also reduce the risk of transmission of HIV-1 from mother to child three- to fourfold independently of zidovudine treatment, supporting a role of the placenta in preventing HIV-1 transmission during gestation.4

The placenta is composed of fetal capillaries, placental macrophages (Hofbauer cells), and cytotrophoblasts surrounded by syncytiotrophoblasts to form a functional subunit, the placenta villous. The barrier between maternal and fetal circulation (and ultimately HIV-1 transmission) is several cell layers thick and consists of syncytiotrophoblasts, Hofbauer cells, and intervening stroma. It is controversial whether syncytiotrophoblasts are susceptible to HIV-1 infection although syncytiotrophoblasts were shown to be infected in vitro by co-culture with virus-infected maternal lymphocytes; a process enhanced by antibody.5-8 In another study, trophoblasts grown in primary culture were, however, not infectable by free virus but supported replication of virus introduced by transfection.9 Given that syncytiotrophoblasts may not be infectable by free virus, other mechanisms such as structural disruptions in the syncytiotrophoblasts, endocytosis of viral particles, or active transport of HIV-1 immune complexes via Fc or complement receptors have been proposed for transplacental passage of HIV-1.10-12 Functional gene transfer of HIV-1 DNA by uptake of apoptotic bodies, independently of free virus and HIV-specific receptors, was recently demonstrated.13 This mechanism might be another alternative to explain transplacental passage/infection of syncytiotrophoblasts. After penetrating the trophoblast layer, HIV-1 encounters cells expressing HIV-1 co-receptors such as lymphocytes and macrophages. Placental macrophage-like cells (Hofbauer cells) support HIV-1 replication of both CCR5-using (R5) and CXCR4-using (X4) isolates as well as primary isolates.14,15

Numerous studies comparing maternal HIV-1 isolates to those transmitted to their children reveal transmission of a selected, homogeneous population of HIV-1 isolates16-18 although not all agree.19 Although most studies agree that some form of selection occurs during vertical transmission, few studies have identified the placenta as being involved in this selection process. No studies to date have identified the mechanism underlying the selection process in the placenta. Here, we investigate one possible mechanism for HIV-1 selection in the placenta.

Previously, we have shown in vitro and in vivo that chemokine receptor expression on immune cells is regulated by type 1 and type 2 cytokines.20-22 Type 1 cytokines such as interferon-{gamma} or interleukin (IL)-2 up-regulate both CCR5 and CXCR4 mRNA and protein expression whereas Type 2 cytokines such as IL-4 and IL-10 up-regulate CXCR4 mRNA and protein expression without affecting or decreasing CCR5 mRNA or protein expression.21 We hypothesize that this mechanism effectively functions in the placenta.

Here we describe profound differences in chemokine receptor expression between placentae from HIV-1 transmitting and nontransmitting women. These different expression patterns can be attributed to distinctly different cytokine milieus in transmitting placentae compared to nontransmitting placentae. We also demonstrate that differential chemokine receptor expression selects for productive infection of cell type expressing the predominant receptor. This selection based on chemokine receptor expression is consistent with the predominance of R5, nonsyncytium-inducing isolates in perinatally infected children.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Participants

Placenta samples were obtained from 23 HIV-1-infected women including 16 from nontransmitting women (TNT) and seven placentae from transmitting women (TT). The tissues were obtained from women at the time of normal vaginal delivery after consent. In addition, term placentae from HIV-1-seronegative women devoid of inflammation or other pathology were used as normal controls. TT women were matched with TNT women for maternal CD4 count, placenta gestational age, and age. None of these women had any antiretroviral therapy during pregnancy. Only women with the w/w CCR5 genotype were selected for this study. The Ethical Review Committee approved the study protocol.

Tissue and Cell Preparation

Tissue samples were homogenized for RNA extraction, snap-frozen in OCT embedding compound, or fixed in Streck tissue Fixative (Streck Laboratories, Omaha, NE). RNA was extracted from biopsy specimens by homogenizing fresh biopsies of 5 mm3 in 500 µl of TriReagent using diethyl pyrocarbonate-treated, autoclaved, disposable homogenizers. After homogenization RNA was purified as per the manufacturer’s protocol. RNA pellets were resuspended in 1x transcription buffer (Promega, Madison, WI) with 2 units RQ1 RNase-free DNase. DNA was digested for 30 minutes at 37°C to remove contaminating DNA. The mixture was extracted once with phenol:chloroform:isoamyl:alcohol, and once with chloroform:isoamyl:alcohol. The aqueous layer was removed and the RNA was precipitated in 3 volumes of ethanol and 1/40 volume of 3 mol/L of sodium acetate overnight at -20°C.

Immunohistochemistry/in Situ Image Analysis

Tissue sections were cut to 8 µm, adhered to silanized slides, and deparaffinized through xylenes and graded alcohols. After peroxidase quenching and blocking with mouse serum in phosphate-buffered saline (PBS), pH 7.4, with 5% nonfat dry skim milk, immunohistochemistry was performed using the Vectastain ABC-HP kit (Vector Laboratories, Burlingame, CA) as per the manufacturer’s recommendations. Diaminobenzidine was used as substrate with hematoxylin counterstain. Frozen tissue sections for quantitative image analysis were allowed to air-dry for 15 minutes and were followed by postfixation in 2% formaldehyde for 20 minutes. Sections were washed in PBS and an optimized dilution of primary antibody was applied. Commercially available antibodies to IL-2, IL-4, IL-10 (PharMingen, San Diego, CA) were used at concentrations optimized on control tissues. Quantitative assessments of the staining for chemokine receptors CCR5 (45549.11/45531.111 mouse IgG2b) and CXCR4 (44717.111, mouse IgG2b) were obtained from R&D Systems (Minneapolis, MN). The sections were stained without the primary mAb to control for nonspecific background. Irrelevant isotype-specific antibodies; rabbit anti-mouse IgG1, IgG2b, and rabbit anti-rat were used to control for nonspecific staining reactions. The staining procedure was performed as previously described.23 Cytokine and chemokine expression was quantified using in situ image analysis as previously described.23

Chemokine Receptor and Cytokine mRNA Quantification

Quantitative real-time reverse transcription polymerase chain reaction was performed by adding 45 µl of the reaction mix, which includes 1x RT Taqman EZ buffer (PE Applied Biosystems, Foster City, CA), 4.0 mmol/L Mn(OAc)2, 300 µmol/L dATP, 300 µmol/L dCTP, 300 µmol/L dGTP, 300 µmol/L dTTP, 200 nmol/L upstream primer, 200 nmol/L downstream primer, 200 nmol/L internally-conserved fluorogenic probes, and 10 units rTth polymerase, directly to 200 ng of total RNA in 5 µl of RNase, DNase-free water (Ambion, Austin, TX). Input RNA was normalized using glyceraldehyde-3-phosphate dehydrogenase mRNA quantification (PE Applied Biosystems). Reverse transcription and thermal amplification were performed using the following linked profile: reverse transcription 30 minutes at 60°C, cDNA denaturation 5 minutes at 95°C, and 40 cycles of denaturation (95°C for 15 seconds) and annealing/extension (60°C for 1 minute) in a 7700 sequence detection system (PE Applied Biosystems). Duplicate standard curves with copy number controls ranging from 10 copies to 105 copies were run with each optical 96-well plate (PE Applied Biosystems). In addition, no template controls were included with each plate. Primer and probe sequences have been previously described.20

Immunophenotyping/Fluorescence in Situ Hybridization

Tissue frozen in OCT embedding compound (Fisher Scientific, Pittsburgh, PA) were cut to 5 µm and adhered to silanized slides (PE Applied Biosystems) followed by simultaneous immunophenotyping/fluorescence in situ hybridization as previously described.24 Briefly, the sections were air-dried, rehydrated in PBS, and labeled with optimized concentrations of phycoerythrin-conjugated antibodies specific for the cell type of interest (CCR5, CXCR4) (PharMingen, San Diego, CA). HIV-1 mRNA was detected in the tissues using the ViroTect In Cell HIV-1 Detection System (Invirion, Frankfort, MI). The probe was hybridized to the target sequence for 60 minutes at 43°C, in a GeneAmp 1000 slide cycler (PE Applied Biosystems). Multiparameter analysis of cell surface receptors and HIV gag-pol mRNA was performed on a laser confocal microscope (Olympus, Melville, NY). Quantification of viral copies was performed using Metamorph software and fluorescein equivalents bead standards (Flow Cytometry Standards, San Juan, PR) and the formula:

*Based on 142 fluorescein equivalents per HIV-1 copy.

Statistical Analysis

Comparisons between transmitting and nontransmitting placentae were performed using either the Mann-Whitney rank sum test or paired t-test. Comparisons yielding a P < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Chemokine Receptor Expression in the Placenta

Total placenta RNA was extracted from 16 TNT and seven TT as well as four normal controls (Table 1) . Real time reverse transcriptase-polymerase chain reaction was used for quantification of chemokine receptor expression. The CCR5:CXCR4 ratio was significantly increased in the TT placentae compared to TNT and normal controls. The number of CCR5 mRNA copies increased two- to threefold (P < 0.01) and the number of CXCR4 mRNA copies were reduced by half in the TT placentae compared to TNT and normal controls (P < 0.02, Table 1 ).


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  		Table 1. Quantification of mRNA in TT, TNT, and Normal Control Placentae

 
CXCR4 and CCR5 protein-expressing cells were analyzed at the single-cell level by in situ imaging in sections stained by immunohistochemistry (Figure 1, A and B) . Quantification by in situ imaging showed that CXCR4 protein-expressing cells were present in equivalent numbers in TNT placentae compared to TT placentae. Conversely, CCR5 protein expression was up-regulated threefold in TT placentae compared to TNT placentae (P < 0.02). Chemokine receptor-positive cells were confined to placental macrophages and lymphocytes on the fetal side of the placenta villous (Figure 1A) . Trophoblasts did not express either CXCR4 or CCR5 protein.



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  		Figure 1. Representative quantification and localization of CCR5, CXCR4, and cytokine protein expression in placentae from transmitting and nontransmitting women using immunohistochemistry (A) and assisted computerized image analysis (B). Cells staining with a brown precipitate express the protein indicated (arrows). Cells were counterstained blue with hematoxylin. Chemokine receptor protein was expressed in placental lymphocytes and macrophages (Hofbauer cells) but not in trophoblasts. Scale bar, 20 µm.

 
Characterization of the Cytokine Milieu in Placenta

It has been previously reported that type 1 and type 2 cytokines are involved in the regulation of chemokine receptor expression.21 To determine whether the chemokine receptor expression pattern observed in the placenta was associated with locally produced cytokines, real-time reverse transcriptase-polymerase chain reaction gene quantification and in situ imaging were used to quantify cytokines in placenta tissue. In TNT placentae, there was a significant elevation of type 2 cytokine (IL-4 and IL-10) mRNA relative to type 1 (IL-2) mRNA expression (P < 0.02, Table 1 ). This cytokine pattern with a dominance of type 2 over type 1 cytokines was also observed in normal controls. The cytokine pattern observed in TT placentae was, on the other hand, reversed with an up-regulation of IL-2 and a down-regulation of type 2 cytokines compared to TNT placentae or normal control (all P < 0.05).

To confirm translation of cytokine mRNA into protein, tissue sections were stained by an immunohistochemistry technique and the local intracellular expression of cytokines was measured by in situ imaging. Type 2 cytokine (IL-4 and IL-10)-expressing cells were significantly up-regulated in TNT placentae compared to TT placentae (P < 0.02) (Figure 1, A and B) . Biopsies from TT placentae showed significantly higher frequency of IL-2-expressing cells compared to TNT placentae (P < 0.05; Figure 1, A and B ).

Chemokine Receptor Expression of Placental Cells Productively Infected by HIV-1

A sensitive in situ hybridization technique was used simultaneously with immunophenotyping to confirm selective utilization of chemokine receptors by HIV-1 in infected tissues.21 The transmitting placenta had a statistically significant increase in the number of gag-pol mRNA expressing cells as determined by quantitative laser confocal microscopy (2.3% versus 0.02%, P < 0.001) (Figure 2) . More than 99% of cells expressing gag-pol mRNA were CCR5-positive cells in TT placenta samples. Conversely, a minority (<10%) of productively HIV-1-infected cells in the TNT placentae expressed CCR5 whereas the great majority of productively HIV-1-infected cells expressed CXCR4.



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  		Figure 2. Representative quantification and localization of cells expressing CCR5 or CXCR4 and HIV-1 gag-pol mRNA using UFISH with simultaneous CCR5 or CXCR4 immunofluorescence. Cells expressing CCR5 or CXCR4 alone appear red, cells expressing HIV-1 gag-pol mRNA appear green, and cells expressing both CCR5 or CXCR4 and HIV-1 gag-pol mRNA appear yellow-white depending on the amount of HIV-1 in the cell. The number of cells expressing HIV-1 gag-pol mRNA (green-white) and the number of HIV-1 copies per average infected cell were compared in TT (A), TNT (B), and normal placentae (C). Productively infected cells in TT placentae averaged 2.3% of mononuclear cells compared to 0.02% mononuclear cells in TNT placentae. Greater than 99% of productively infected cells in TT placentae were CCR5+ (A, arrowheads) whereas the majority of rare productively infected cells in TNT placentae were CXCR4+ (B, arrow). Productively infected cells in TT placentae average 214 HIV-1 copies per cell compared to 78 HIV-1 copies found in productively infected cells from TNT placentae suggesting an inhibition of HIV-1 replication in the TNT placentae. Dotted circles represent placental villi. Percentages and viral counts were based on the scanning of 10 fields with a surface area of 125.6 mm2 each.

 
Based on a standard curve using fluorescein equivalent bead standards and the formula described in the Methods section, we calculated the number of viral copies per cell in TT and TNT placentae. Productively HIV-1-infected cells in the TT placentae averaged 214 viral copies per cell whereas productively HIV-1-infected cells in TNT placentae averaged 78 copies per cell demonstrating quantitative differences in HIV-1 production as well as tropism differences in TNT placentae compared to TT placentae.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Numerous studies comparing HIV-1 gene sequences of mother-child-paired peripheral blood samples have described transmission of a homogeneous subset of maternal isolates.16-19 Although these types of studies continue to shed additional light on the nature of vertically transmitted HIV-1 isolates; little has been published examining the selective pressures in the placenta or birth canal that may influence transmission. Many factors have been proposed that influence maternal-fetal transmission. Factors associated with vertical transmission can be divided into maternal factors such as maternal viral load,25-27 maternal neutralizing antibody,28-31 or maternal HIV-1-specific cytotoxic T cell activity;32 maternal-placenta interface factors such as FasL expression33-35 or tumor necrosis factor-related apoptosis-inducing ligand/Apo-2L expression;36 placental factors such as chorioamnionitis37,38 or HIV-suppressive activity;39,40 or fetal factors such as neutralizing antibodies or HIV-specific cytotoxic T cell.41-43 Here we present data to support an additional placental factor, that is, a type 2 to type 1 placental cytokine milieu shift drives chemokine receptor expression that selects for isolates demonstrated in numerous sequencing studies to be more likely transmitted.

Cytokines have been shown to increase or decrease HIV replication.44 Previous studies of cytokine expression in the placenta have revealed production of a variety of type 1, type 2, and proinflammatory cytokines.45-52 The cytokine milieu of the placenta and the hormonal-cytokine network at the maternal-fetal interface has a crucial role in preventing fetal allograph rejection and supporting implantation. Allograph rejection is mediated by type 1 cytokines including interferon-{gamma} and tumor necrosis factor-ß.52 Several studies support the hypothesis that production of type 2 cytokines (IL-4, IL-10) may permit allograph tolerance and maintenance of pregnancy.45,46 Factors promoting a shift from a protolerance to a prorejection milieu remain to be fully characterized but may include infection, trauma, and vascular compromise. Evidence that HIV infection may create a prorejection milieu is supported by the increased risk of spontaneous abortion in HIV-infected women.53 Our data suggest that placentae from nontransmitting women maintain a normal type 2 placental cytokine milieu whereas transmitting women have placentae that express type 1 cytokines. The mechanism underlying a shift from a type 2 cytokine dominance to a type 1 cytokine dominance in TT placentae is not clear although TT placentae tended to exhibit more chorioamnionitis or villitis. Because the type 1 cytokine milieu in placentae from transmitting women does not result in spontaneous abortion, the type 2 to type 1 shift in cytokine expression is likely to be a late event. This is consistent with transmission during the third trimester and supports the efficacy of third trimester antiretroviral therapy.

The CCR5 chemokine receptor is required by nonsyncytium-inducing HIV-1 strains to infect target cells. Nonsyncytium-inducing isolates are the predominantly transmitted isolates from mother to infant. The role of CCR5 in vertical transmission has been predominantly studied in the context of genotype.54,55 These reports indicated that the presence of the homozygous {Delta}32 or heterozygous genotype among children of HIV-infected mothers has a protective role in transmission of HIV-1. For the first time, we here describe the role of CCR5 expression levels in selection for vertical transmission. Furthermore, we demonstrate that the type 2 cytokine milieu that predominates in normal full-term pregnancies and placentae from nontransmitting HIV-seropositive mothers drives the expression of CXCR4 resulting in a normally low CCR5:CXCR4 ratio in placental tissues. In addition, preferential up-regulation of CXCR4 mRNA by IL-10 occurs in in vitro cultures of placental-derived macrophages (B. K. Patterson, et al unpublished data). The observed up-regulation of CXCR4 could also be mediated by progesterone which was shown in a previous study by our laboratory to preferentially up-regulate CXCR4 production in peripheral blood mononuclear cells.20 Taken together, these data strongly support the hypothesis that the normal placental milieu selects for isolates of HIV-1 less likely to be transmitted and, conversely, placental pathology selects for isolates that preferentially replicate in CCR5-expressing cells and consequently are more likely to be transmitted.

In situ imaging demonstrated that CCR5 and CXCR4 are expressed on placental macrophages and lymphocytes but not in trophoblasts. Simultaneous immunofluorescence in situ hybridization for HIV-1 gag-pol mRNA revealed that HIV-1 almost exclusively infects HIV-1 CCR5-expressing cells in placentae from transmitting women whereas HIV-1 infects predominantly CXCR4-expressing cells in nontransmitting placentae. A statistically significant increase in the total number of productively infected cells and in the number of viral particles produced per cell was also demonstrated in TT placentae compared to TNT placentae. These data suggest that the type 2 cytokine milieu and concomitant low CCR5:CXCR4 ratio may prevent HIV-1 replication in the placenta although the opposite is found in peripheral blood mononuclear cells. Conceivably, the normal placental cytokine environment may up-regulate ß-HCG, a known inhibitor, or recently identified inhibitors of HIV-1 replication (B. K. Patterson, unpublished data). Our data, however, directly support previous studies that indicate vertical transmission of a homogeneous subset of maternal HIV-1 isolates that are nonsyncytium-inducing and use CCR5 as co-receptor.

In summary, our results indicate that immune-based interventions aimed at ways to augment the placentae ability to prevent transmission may provide cost effective prevention strategies accessible to populations without access to drug therapy.


   Footnotes
 
Address reprint requests to Bruce K. Patterson, M.D., Department of Pediatrics, Division of Infectious Diseases, Children’s Memorial Hospital, Northwestern University Medical School, 2300 Children’s Plaza #51, Chicago, IL 60614. E-mail: bpatterson{at}childrensmemorial.org

Supported by grants from amFAR (grant no. 02633-26-RGI), the Swedish Medical Research Council (grant no.10850), the National Cancer Institute (grant no. 2490), the National Institutes of Health (grants nos. AI 41536-01 and AI 47065), and the Swedish Physicians Against AIDS Research Foundation.

Accepted for publication August 24, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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