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Increase in HIV Receptors/Co-receptors/
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-defensins in Inflamed Human Gingiva |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Transmission of HIV-1 through the oral cavity is considered to be a rare event. To identify factors in resistance/susceptibility to oral HIV-1 infection, we analyzed expression in human gingiva of HIV-1 receptors Langerin, DC-SIGN, MR, and GalCer, HIV-1 co-receptors CCCR5, CXCR4, and anti-microbial protein
-defensin-1. Our results show that healthy gingiva is infiltrated with cells expressing all HIV-1 receptors tested; however, there are very few CCR5+ cells and a complete absence of CXCR4+ cells in the lamina propria. In chronic periodontitis (CP), DC-SIGN, MR, CXCR4, and CCR5 increase, but this was accompanied by a ten-fold increase in -defensin-1 mRNA. The CCR5+ cells were revealed to be T-cells, macrophages, and dermal dendritic cells. Moreover, epithelial expression of GalCer and CXCR4 together was not apical and showed no trend with underlying inflammation. Thus, low expression of HIV-1 co-receptors in health and high expression of -defensin during CP may comprise endogenous factors that provide protection from oral HIV-1 infection.
Key Words: HIV receptor • co-receptor • DC-SIGN • CCR5 • -defensin-1 • dendritic cells • gingiva • human
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Although most HIV-1 cases worldwide are transmitted through mucosal surfaces, their transmission through oral mucosa and its secretions is uncommon (Rothenberg et al., 1998; Cohen et al., 2000). Oral fluids contain many factors that protect the oral tissues from infection and reduce the risk of viral transmission (Shugars et al., 2002). Despite this, antiviral mechanisms in the oral cavity are not impenetrable. Factors in seminal fluid, milk, blood, and blood proteins can protect HIV-1 from the killing effects of saliva (Baron et al., 2000). Human oral epithelial cells, like other epithelia, can be infected with HIV-1 in vitro (Liu et al., 2003). Nonetheless, the limited oral transmission of HIV-1 suggests that additional endogenous antiviral mechanisms in oral mucosa protect it from infection.
The main cells in gingiva that can express HIV-1 receptors/co-receptors are dendritic cells (DCs), CD4+ T-lymphocytes, and macrophages. Studies from our laboratory demonstrate that oral mucosa contains at least two DC subsets: Langerhans cells (LCs) and dermal DCs (DDCs) (Jotwani and Cutler, 2003). Recent evidence suggests that HIV-1 uses receptors belonging to the mannose C-type lectin receptor (MCLR) family to attach to different DC subsets (Turville et al., 2002). It includes DC-specific ICAM-3 grabbing non-integrin (DC-SIGN), expressed by DDCs, macrophage mannose receptor (MR), expressed by DDCs, and macrophages and Langerin, expressed by LCs. However, the in vivo relevance of these receptors in HIV-1 pathogenesis is uncertain. HIV-1 enters CD4+ T-lymphocytes and macrophages via CD4 in conjunction with chemokine receptors CCR5 and or CXCR4. Human studies indicate that gingival inflammation, i.e., CP, results in increased numbers of CD4+, CD8+ T-cells, and CD83+ mature DCs in the lamina propria, and increased production of pro-inflammatory cytokines (TNF- and IL-1β) associated with bone loss (Jotwani et al., 2001; Graves and Cochran, 2003). Pro-inflammatory cytokines support the replication of HIV-1 and induce up-regulation of CCR5 expression on macrophages and CD4+ T-cells (Juffermans et al., 2000; Kedzierska et al., 2003). However, surface expression of HIV-1 receptors/co-receptors in human gingiva during health and CP is presently unclear.
Resistance to HIV-1 infection in human gingiva can also be mediated by antimicrobial proteins, the defensins. It has been observed that synthetic as well as purified preparations of -defensins from neutrophils are sufficient to inhibit HIV-1 replication in vitro (Zhang et al., 2002; Chang et al., 2003; Mackewicz et al., 2003). -defensin mRNA has been documented in gingiva (Dunsche et al., 2001), and its presence in human gingival neutrophils, which protect undifferentiated junctional epithelium, has also been shown (Dale et al., 2001; Dale, 2002). Quantitation of -defensins during health and disease may provide information regarding the degree of protection they afford to the gingiva.
In the present study, we investigated the expression pattern of HIV-1 receptors/co-receptors and -defensins by human gingiva during health and CP. We used single- and double-immunolabeling, combined with image-enhanced fluorescence microscopy, and real-time PCR. We found that oral mucosa harbors many cell types that express HIV-1 receptors, including LCs in the epidermis, and DDCs, T-cells, and macrophages in the lamina propria. Interestingly, expression of the HIV-1 co-receptor CCR5 was very low, and there was complete absence of CXCR4 by these resident cells in lamina propria of healthy gingiva. During CP, the number of cells expressing DC-SIGN, MR, CXCR4, and CCR5 increased; the CCR5+ cells were revealed to be T-cells, macrophages, and DDCs. There was also a ten-fold increase in expression of -defensin-1 in CP. Non-CD4 HIV-1 receptor galactosylceramide (GalCer) and co-receptor CXCR4 together were expressed in deeper epithelial layers closer to the basal layer and showed no trend with underlying inflammation.
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Collection, Preparation, Specimen Staining, Cell Counting
Gingival tissue was obtained under informed consent from chronic periodontitis (CP) subjects (n = 12) and healthy adult controls (n = 8) previously described (Jotwani et al., 2001). The Institutional Review Board for protection of human subjects approved this protocol.
Single immunoenzyme staining was performed on pre-fixed frozen sections, as described (Jotwani et al., 2001). Sections were stained by the biotin-streptavidin- peroxidase method (Vectastain ABC Elite kit, Vector Laboratories Inc., Burlingame, CA, USA). The primary antibodies used are listed in (Table
). The specificity of staining was confirmed with isotype control antibodies. To quantitate inflammation and HIV receptors, we scanned 20x fields using Image Pro software and expressed the data as # cells/20 field. Data were analyzed for statistical significance by Student’s t test.
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For double-immunofluorescence staining, slides were rehydrated, blocked, and incubated for 1 hr at room temperature with primary mouse monoclonal antibodies (mAB) to CCR5, CD4, and CD68. After being washed, slides were incubated for 30 min at room temperature with Texas Red/FITC-conjugated goat antibodies to mouse immunoglobulin (Molecular Probes Inc., Eugene, OR, USA). In a subsequent secondary step, FITC/Texas Red-conjugated mAB to CD4, CD68, and DC-specific ICAM-3 grabbing non-integrin (DC-SIGN) were used. The specificity of the primary and secondary antibodies was confirmed with the respective isotype controls. Images were sharpened with the use of 2-D deconvolution software.
Quantitation of -defensin-1
Primers for amplification of -defensin-1 and β-actin were designed with primer3 software to give an amplified product in a range of 150–200 bp. Conventional RT-PCR was performed to confirm the purity of the amplified product, and quantitative real-time PCR (iCycler Bio-Rad, Hercules, CA, USA) quantitated expression of -defensin-1 mRNA. All quantitations were performed in triplicate, and the means of the transcript initial concentrations were normalized with the means of the β-actin values for each sample. The normalized initial concentration of each transcript in each sample was converted to initial copy number according to the formula: Amount (copies/µL) = 6 x 1023 (copies/mol) x concentration (g/µL)/*Molecular weight (g/mol) (*Average molecular weight of ds DNA = number of base pairs x 660 Daltons/base pair)
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Expression of HIV-1 Receptors/Co-receptors in Human Gingiva during Health
Cells bearing the HIV receptors DC-SIGN, MR, and Langerin were observed in non-inflamed human gingiva (Fig. 1A
). Langerin was restricted to epithelium, DC-SIGN and MR to the lamina propria. The identity of cells expressing Langerin and DC-SIGN (i.e., LCs and DDCs, respectively) has previously been confirmed (Jotwani and Cutler, 2003). Interestingly, we observed that there are very few HIV-1 co-receptor CCR5-positive cells and a complete absence of CXCR4 in the lamina propria of healthy gingiva (Fig. 2E1). Expression of CXCR4 and GalCer was limited to the epithelium in health (Figs. 2E1, 2E2), but their expression patterns differed. GalCer was observed in discontinuous patches distributed uniformly throughout the depth of the epithelium (Fig. 2E2). CXCR4 was expressed more in the deeper layers of epithelium, closer to the basal layer, far from differentiated spinous/squamous surface-associated layers (Fig. 2E1).
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Increased Numbers of Cells Express HIV-1 Receptors and Co-receptor CCR5 during CP
In the inflamed gingiva (Fig. 1B
), we observed a significant increase in numbers of DC-SIGN+ cells (Fig. 1C) and a trend for increased MR (Fig. 1E). Both DC-SIGN and MR are significantly associated in a linear fashion with gingival inflammation (Figs. 1D, 1F). The expression of Langerin in inflammation shows a trend for decreasing (Fig. 1H). This is consistent with the efflux of Langerhans cells out of the epithelium to the lamina propria in response to inflammatory signals. Further, we see a significant increase in CCR5+ cells in CP (Figs. 2A2, 2F), in a linear association with inflammation (Fig. 2G). Double-immunofluorescence labeling of inflamed gingiva reveals expression of CCR5 by T-cells (Fig. 2B), macrophages (Fig. 2C), DDCs (Fig. 2D), and some basal layer epidermal cells (Figs. 2B, 2C). Furthermore, we observed expression of CXCR-4 (but not GalCer)-positive cells in the lamina propria of isolated cases of CP (Fig. 2E5), in the same region where we found increased expression of CCR-5 (Fig. 2E6). Expression of CXCR-4 and GalCer in the epithelium showed no apparent trend with underlying inflammation.
Expression of -defensin-1 in Human Gingiva during Health and Disease
Expression of -defensin-1 in human gingiva by RT-PCR demonstrated a single band of 169 bp by agarose gel electrophoresis, confirming the purity of the amplified product (Fig. 3A). Quantitation of -defensin mRNA by real-time PCR revealed expression during health (n = 8) and demonstrated a ten-fold increase in mean copy number during inflammation (n = 8) (Fig. 3B).
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10-fold) in mean copy numbers of |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Oral mucosal factors in gingiva which can contribute to their resistance/susceptibility to HIV-1 infections are not very well-understood. We observed that oral mucosa harbors cells that express many HIV-1 receptors, including DC-SIGN, MR, and Langerin (Fig. 1A
). Interestingly, we observed that there are very few CCR5-positive cells and a complete absence of other HIV co-receptor CXCR4 in the lamina propria of healthy gingiva (Figs. 2A1, 2E1, respectively). Co-receptor expression is critical to HIV infection, as is clearly demonstrated by inherent resistance to HIV infection in individuals expressing a homozygous deletion in mutation in the CCR5 gene (Huang et al., 1996). It is generally believed that expression and regulation of HIV receptor/co-receptors at different anatomic sites (Zhang et al., 1998; Jameson et al., 2002) govern their susceptibility or resistance to infection with HIV-1. For example, the risk of HIV-1 transmission is greater in rectal intercourse than in vaginal exposure. In the rectum, numerous DC-SIGN+CCR5+CD4+ DCs and CD4+CCR5+ T-cells are expressed throughout the lamina propria beneath the luminal epithelium, whereas vaginal subepithelial DCs in the lamina propria express moderate levels of DC-SIGN, and a small number of these cells co-express CCR5 (Jameson et al., 2002). In view of these observations and the results of the present study, it may be quite reasonable to presume that low expression of HIV co-receptors during health in oral mucosa may play a role in resistance of gingiva to infection with HIV-1.
Resistance to HIV-1 infection in the human gingiva can also be mediated by antimicrobial proteins, the defensins. Analysis of -defensin-1 mRNA expression in human gingiva in the present study demonstrates their expression during health (Fig. 3). Several studies have independently confirmed the anti-HIV potential of -defensins-1–3 (Zhang et al., 2002; Chang et al., 2003; Mackewicz et al., 2003). Anti-HIV activity of -defensins has been shown to operate on at least two levels, direct inactivation of virus particles and inhibition of the ability of target CD4 cells to replicate the virus (Mackewicz et al., 2003). Purified concentrations of HNP inhibitory to HIV-1 were non-cytotoxic to CD4 T-cells (Zhang et al., 2002; Chang et al., 2003), except in one study (Mackewicz et al., 2003) in which they observed a 40% cytotoxicity. Higher cytotoxicity could have resulted from a high concentration (100 µg/mL) of defensins used. Recently, it has been shown that human β-defensins (HBD) 2 and 3, which are produced by human oral epithelial cells, can also block HIV-1 replication via a direct interaction with virions and through modulation of the CXCR4 co-receptor in vitro (Quinones-Mateu et al., 2003). HBD-2 and HBD-3 are expressed during health, but only in human gingiva (Dale et al., 2001). In most other tissues, they are expressed during infection or inflammation (Wehkamp et al., 2002). Constitutive expression of HBD-2 (10 µM/gram of tissue) is sufficient to inhibit replication of the HIV-1 X4 isolate (Sawaki et al., 2002l Quinones-Mateu et al., 2003). Studies have shown that both - and β-defensins are sensitive to high salt and serum concentrations (Mackewicz et al., 2003; Quinones-Mateu et al., 2003). However, in oral mucosa, defensins may encounter HIV and function under low salt and serum conditions (Mandel, 1972). In saliva, the salt concentrations are low and, depending on flow rate, range from 1 to 60 µM (Smith, 1996).
Our results demonstrate that, during gingival inflammation, there is an increase in cells co-expressing CCR5 and HIV receptors CD4, DC-SIGN, or MR (Figs. 2B, 2C). Similar observations have been reported in inflamed vaginal and rectal mucosal surfaces. Inflammation at those mucosal surfaces has been considered as a risk factor for HIV-1 infection for several reasons, including the fact that ulceration eliminates the barrier effects of an intact epithelium and exposes the full range of target cells in the lamina propria that express viral receptors/co-receptors to the infectious virus (Miller and Shattock, 2003). Studies in women have shown that vaginal inflammation, i.e., vaginitis, increases the expression of CCR5 on T-cells, macrophages, and DCs and thus appears to be a key determinant of susceptibility to HIV-1 (Rottman et al., 1997; Zhang et al., 1998). In the present study, we also show significant increases (~ 10-fold, p < 0.05, Student’s t test) in mean copy number x 106 of -defensins, known to have anti-HIV activity. The -defensins have previously been shown to be CD8+ T-cell-derived antiviral factors (Zhang et al., 2002); however, subsequent studies have rebutted that claim (Chang et al., 2003; Mackewicz et al., 2003). Additional cell sources of -defensins include neutrophils, NK cells, 
T-cells, monocytes, and B-cells (Agerberth et al., 2000; Mackewicz et al., 2003). Several of these cell types increase during CP, and establishing which produce -defensins in addition to neutrophils needs further investigation. Furthermore, studies have shown that expression of HBD2 and HBD3 is also up-regulated during inflammation (Dale, 2002; Quinones-Mateu et al., 2003). These observations suggest that human gingiva contains multiple endogenous factors which could be sufficient to provide resistance to HIV-1 infection during health and disease.
In vitro studies have shown that oral epithelial cells do not express CD4 but instead express GalCer (which acts as a receptor for HIV-1) and also express HIV co-receptors CCR5 and/or CXCR4. Despite a growing number of reports, the issue of HIV infection of oral epithelial cells remains debatable. One report found no infection (Quinones-Mateu et al., 2003), another found infection by CXCR4 tropic and dual tropic HIV strains (Liu et al 2003), whereas infection with only R-5 tropic strain but not with CXCR-4 tropic strain is also reported (Moore et al., 2003). The present study demonstrates that healthy gingiva express both GalCer and CXCR4, but together they may be expressed only in the deeper layers, closer to the basal epithelial layer, suggesting lower possibility of serving as HIV target. In the colonic epithelium, there is a predominant apical expression of CXCR4 and CCR5, which can serve as a target for entry of HIV-1 across the colonic mucosa (Dwinell et al., 1999). However, further in vivo as well as in vitro studies with a physiologically relevant model of oral mucosa will be required to investigate epithelial cells and HIV interaction under highly controlled conditions.
In conclusion, we have demonstrated that, overall, in gingival health, the expression patterns of HIV-1 receptors/co-receptors apparently do not favor infection with HIV-1. During CP, however, there is an increase in the number of cells co-expressing HIV-1 receptors/co-receptors, but this is accompanied with ten-fold increases in -defensin-1, known to have potent anti-HIV-1 activity. Further studies are required to clarify the role of defensins (both and β) in oral mucosa so that protection strategies at other mucosal surfaces can be designed.
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ACKNOWLEDGMENTS |
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This study was supported by a US Public Health Service grant from the NIH/NIDCR (R01 DE14328) and was aided by a small-equipment grant from the Targeted Research Opportunities Program, University Medical Center, SUNY-Stony Brook, NY. Special appreciation is extended to Drs. P. Baer, A. Ienna, V. Iacono, and the post-graduate Periodontology residents for contributing to the gingival specimens.
Received for publication December 1, 2003. Revision received February 25, 2004. Accepted for publication February 27, 2004.
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Journal of Dental Research, Vol. 83, No. 5,
371-377 (2004)
DOI: 10.1177/154405910408300504
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