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1 Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University (CWRU), 10900 Euclid Ave., Cleveland, OH 44106, USA
2 Lerner Research Institute, Cleveland Clinic Foundation, Center for AIDS Research, CWRU; and
3 University Hospitals of Cleveland, OH
Correspondence: * corresponding author, aaron.weinberg{at}case.edu.
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Abstract |
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 TOP Abstract IntroductionBackgroundHuman Beta-defensins and HIV-1References |
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KEY WORDS: Human beta-defensin • epithelial cell • innate immunity • HIV
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Introduction |
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TOPAbstractIntroductionBackgroundHuman Beta-defensins and HIV-1References |
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Recent findings in the field of innate immunity are shedding new light on the importance of host defense antimicrobial peptides. With the recent discoveries of human ß-defensins (hBDs) in mucosal epithelium, a new line of investigation is emerging to test the hypothesis that these peptides, integral members of the innate host immune response, function to protect the host against microbial pathogenesis at the mucosal barrier. While their antibacterial and antifungal properties are well-established (Weinberg et al., 1998; Zasloff, 2002), new findings point to hBDs acting like chemokines in ’cross-talking’ with the adaptive immune system, and possibly orchestrating immunosurveillance through maturation of dendritic cells. They recruit immature dendritic cells and T-cells by interacting with the chemokine receptor CCR6 (Yang et al., 1999) and, in mice, have recently been shown to activate immature dendritic cells through Toll-like receptor 4 (Biragyn et al., 2002a). Since (1) the constitutively expressed hBD-1 and inducible hBD-2 and hBD-3 are present in normal human oral epithelium and cells (NHOECs) (Krisanaprakornkit et al., 1998, 2000; Weinberg et al., 1998; Dunsche et al., 2002), (2) they are important mediators of innate mucosal defense against microbial infection (Weinberg et al., 1998), (3) these peptides may be involved in immunomodulation of the adaptive immune system (Biragyn et al., 2002a,b), and (4) ß-defensins can impair adenoviral infections (Gropp et al., 1999), we explored the possible role of these molecules in defense against HIV infection. This review describes novel information related to the antiretroviral activity of mucosal beta-defensins.
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Background |
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TOPAbstractIntroductionBackgroundHuman Beta-defensins and HIV-1References |
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Several explanations have been suggested to explain the paucity of oral HIV-1 infection: (i) a thick multilayered mucosal surface (first line of defense against microbial invasion), (ii) low salivary HIV-1 titers (Ho et al., 1985), and (iii) endogenous antiviral factors present in oral secretions (Fultz, 1986; Shugars, 1999). During the last 15 years, multiple studies have been conducted to identify the source(s) and identity of HIV-inhibitory activity in the saliva of healthy and infected individuals (Fultz, 1986; McNeely et al., 1995; Wahl et al., 1997; Baqui et al., 1999; Becquart et al., 1999; Shugars, 1999; Pillay et al., 2001). Many endogenous inhibitors of HIV-1 in saliva have been proposed (e.g., amylase, lactoferrin, proline-rich peptides, salivary mucins, thrombospondin; and secretory leukocyte protease inhibitor [SLPI], reviewed in Shugars and Wahl, 1998). Moreover, these agents are found in seminal fluid and vaginal secretions, routinely harvested from sites that are very susceptible to infection (Shugars, 1999). Importantly, there is a paucity of information regarding the contributions of innate immune factors emanating from the oral mucosal epithelium itself.
Transmission of HIV-1
A significant genetic bottleneck is apparent during transmission by any route of HIV-1 infection. The selective factors imposing the bottleneck are diverse and likely include: (i) host factors such as innate immune response, (ii) density of target cells and/or their co-receptors at the site of infection, (iii) number of transmitted virions, and (iv) the structure of transmitted viral quasi-species (swarms of mutants). Environmental differences (pH, target cells, mucosal composition) at the site of exposure may affect the efficiency of transmission of the infecting isolates (Overbaugh et al., 1999; Blauvelt et al., 2000). Although there may be an element of chance in the expansion of a particular HIV-1 clone, phenotypic selection does occur in nearly every HIV-1 infection—i.e., selection of R5 isolates occurs in nearly every HIV-1 infection. The heterogeneous HIV-1 envelope glycoproteins have been identified as responsible for two major viral bio-phenotypes: (i) macrophage-tropic non-syncytium-inducing/CCR5-tropic (NSI/R5) HIV-1 isolates, and (ii) T-cell-line tropic isolates, forming cell syncytia during active replication in tumor T-cell lines, which utilize the CXCR4 co-receptor for entry (SI/X4) (Alkhatib et al., 1996; Deng et al., 1996; Dragic et al., 1996; Feng et al., 1996). SI/X4 HIV-1 isolates often dominate the quasi-species late in disease, and yet the NSI/R5 variant is typically transmitted to a newly infected person regardless of the route of transmission (reviewed in Fenyo et al., 2000). Preferential transmission of NSI/R5 over SI/X4 HIV-1 isolates is contradictory to increased replication of SI/X4 HIV-1 over NSI/R5 isolates in culture (Tersmette et al., 1988; Bjorndal et al., 1997). Thus, selectivity of transmission is likely not simply a reflection of replicative fitness, but may also be observed in the transmission of different NSI/R5 HIV-1 isolates in the human population (Blackard et al., 2001). Although in vivo findings suggest that NSI/R5 HIV-1 isolates may out-compete the SI/X4 variants at the site of primary infection, one report suggests that the NSI/R5 isolates predominate only after a temporary expansion of SI/X4 HIV-1 isolates is quenched by an activated immune response (Cornelissen et al., 1995). However, this observation is difficult to reconcile with the finding that humans who are homozygous for a 32-base-pair deletion in the CCR5 open-reading frame, and who lack CCR5 on any cell surface, are typically resistant to HIV-1 infection (Dean et al., 1996; O’Brien and Moore, 2000). To date, the universal factors (i.e., those found in almost every human host) involved in the selection of NSI/R5 HIV-1 isolates during transmission and asymptomatic disease are not well-defined. Langerhans cells (LC) are found embedded in mucosa (i.e., vaginal and oral mucosa) and may be the first cell targets for primary heterosexual transmission (Soto-Ramirez et al., 1996; Blauvelt et al., 2000). Thus, LC may play a role in NSI/R5 HIV-1 selection, since CCR5 is better expressed in situ and in the absence of external stimuli (Blauvelt et al., 2000). For example, a recent report describes increased replication of an NSI/R5 (HIV-1Bal) over an SI/X4 (HIV-1III-B) isolate in LC embedded in skin-derived explants, even though the opposite is true in PBMC cultures or other permissive cell lines (Soto-Ramirez et al., 1996; Blauvelt et al., 2000). However, this is not altogether clear, since another report indicates that CXCR4 is functionally expressed on the surfaces of freshly isolated and unstimulated LC (Tchou et al., 2001).
Defensin peptides and their antiviral activity
The human defensin antimicrobial peptide family, its molecular characteristics, and purported modes of activity are reviewed in Weinberg et al.(1998) and Zasloff (2002). The defensin peptides are a superfamily of peptide antibiotics with a characteristic ß-sheet structure stabilized by two or three intramolecular disulfide bonds. They are strongly cationic by virtue of their numerous arginine and lysine residues. Their amphipathic and cationic characteristics are important for binding to anionic microbial surfaces, such as LPS, through displacement of divalent, lipopolysaccharide (LPS)-associated cell-surface cations, followed by membrane insertion through the ’self-promoted uptake’ pathway (Hancock, 1997) and generation of stable pores (for review, see Weinberg et al., 1998).
There is a paucity of information regarding defensin antiviral effects. What has been published suggests that defensins can inactivate a host of different viruses. Epithelial-cell-derived beta-defensins have been shown to inhibit adenoviral infections (Gropp et al., 1999). Alpha-defensins, found in azurophilic granules of human neutrophils, inhibit adenoviral infection in vitro (Bastian and Schafer, 2001), inactivate cytomegalovirus, vesicular stomatitis virus, influenza virus, and herpes simplex virus 1 and 2, but not two non-enveloped viruses, echovirus type 11 and reovirus type 3 (Daher et al., 1986). Alpha-defensins have also been shown to inhibit HIV replication in vitro (Nakashima et al., 1993; Zhang et al., 2002). Theta-defensins, originally isolated from the rhesus monkey, Macacca mulatta, and not expressed in humans (Tang et al., 1999), were recently shown to prevent infection by T- and M-tropic strains of HIV-1 (Cole et al., 2002). The mode(s) of viral inactivation in all of the cited studies were not determined, and therefore leave a definite void in our understanding of this potentially important biological activity.
ß-defensins and the oral cavity
The recent discoveries that ß-defensins originate in mammalian mucosal epithelium, including human (Diamond et al., 1991; Schonwetter et al., 1995; Zhao et al., 1996; Harder et al., 1997, 2001; McCray and Bentley, 1997; Boe et al., 1999; O’Neil et al., 1999; Haynes et al., 2000; Garcia et al., 2001), has led to the hypothesis that these antimicrobial peptides function to protect the host against microbial pathogenesis at these critical confrontational sites. We have extended this hypothesis to encompass the oral epithelium as well (Krisanaprakornkit et al., 1998, 2000; Weinberg et al., 1998; Dale et al., 2001). This tissue, and cells derived from it, constitutively express hBD-1 and can be induced to express hBD-2 and -3.
The first evidence of ß-defensins in a mammalian oral cavity was described by Schonwetter et al.(1995). The study identified a ß-defensin in the upper surface of the bovine tongue, which was markedly increased in the epithelium surrounding naturally occurring tongue lesions, areas of both acute and chronic inflammation. This agent was shown to be an effective antibacterial and antifungal agent. Since then, we and others have described the presence of ß-defensins in the human oral cavity (Weinberg et al., 1998; Bonass et al., 1999; Mathews et al., 1999; Sahasrabudhe et al., 2000; Dale et al., 2001; Dunsche et al., 2002). In gingival tissue, mRNA for both hBD-1 and -2 was localized in suprabasal stratified epithelium, and the peptides were detected in upper epithelial layers, consistent with the formation of the stratified epithelial barrier (Dale et al., 2001). hBD-1 and -2 were not detected in the junctional epithelium (JE) that serves as the attachment to the tooth surface. In contrast, 
-defensins and LL-37—the only other cationic antimicrobial peptide known to be expressed in most mucosal epithelium, and belonging to the cathelicidin family of antimicrobial peptides (reviewed in Weinberg et al., 1998)—are detected only in the polymorphonuclear neutrophils (PMNs) that migrate through the JE (Dale et al., 2001), a localization that persists during inflammation, when the JE and surrounding tissue are highly infiltrated with PMNs. Therefore, the undifferentiated JE contains exogenously expressed -defensins and LL-37, and the stratified epithelium contains endogenously expressed ß-defensins. Calprotectin, an anionic epithelial cell and PMN-associated antimicrobial peptide, is constitutively expressed in normal oral keratinocytes (Ross and Herzberg, 2001). These findings show that defensins and other microbicidal peptides are localized in specific sites in the gingiva, are synthesized in different cell types, and are likely to serve different roles in various regions of the periodontium.
A notable difference between oral and most other epithelia is the expression of hBD-2 and -3. These defensins are expressed only in the presence of infection or inflammation in most tissues, including skin, trachea, and gut epithelium (O’Neil et al., 1999). However, they are expressed in normal uninflamed gingival tissue (Dale et al., 2001; Dunsche et al., 2002). Present evidence suggests that this baseline level of hBD-2 and -3 could be due to the exposure of the tissue to specific commensal bacteria. Our ongoing work in this area has identified a novel strategy of Fusobacterium nucleatum, whereby this ubiquitous Gram-negative organism of the human oral cavity stimulates hBD-2 and -3 expression in normal human oral epithelial cells (NHOECs)—a result that confers protection to the cells from P. gingivalis invasion (Weinberg et al., unpublished observations; manuscript in review).
Most recently, Lu et al.(2004) demonstrated the expression of hBD-1 and -2 not just in the granular and spinous regions of normal gingival epithelia, but also in the basal cell layers (Fig. 1
). This is significant, since beta-defensins have been shown to possess immunomodulatory activity—such as chemoattraction of immature dendritic cells (iDCs), monocytes, and T-cells (Yang et al., 1999; Wu et al., 2003)—and maturation of iDCs (Biragyn et al., 2002a). Expression of inducible hBDs throughout the oral epithelial mucosa supports the notion that these agents are also involved in ’cross-talk’ with cells of the adaptive immune system. Moreover, the fact that hBDs are also expressed in less-differentiated basally oriented epithelial cells indicates that either differentiation is not essential for hBD expression, as previously suggested (Dale et al., 2001), or that hBD-expressing cells, other than epithelial cells, are infiltrating the oral mucosae. With recent findings that hBD-1 and hBD-2 are also expressed systemically, in human monocytes, macrophages, and dendritic cells (Duits et al., 2002), it is tempting to speculate that they are the source, in part, for hBD expression in the basal lamina.
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Human Beta-defensins and HIV-1 |
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HIV-1 induces hBD-2 and -3 but not hBD-1 mRNA in normal human oral epithelial cells (NHOECs)
NHOEC monolayers were challenged with HIV-1 strains representing both viral bio-phenotypes, i.e., X4 and R5. Both phenotypes were found to induce hBD-2 and -3 mRNA up to 78-fold above baseline (see Quiñones-Mateu et al., 2003). In addition, while HIV-1 can infect epithelial cells from other mucosal surfaces (Yahi et al., 1992; Han et al., 2000; Fotopoulos et al., 2002), we could not detect infection of NHOECs by HIV-1 by viral reverse-transcriptase activity in culture supernatant and after real-time PCR analysis to detect proviral DNA. These results differ from those of Liu et al.(2003), who recently reported low-level replication of the virus after high-dose viral challenge of NHOECs. The discrepancy between their findings and ours may be due to differences in experimental conditions. We omitted polybrene from our infection assays, since this detergent is not physiologic. They also infected cells using a viral inoculum eight times higher than ours. Finally, Liu et al.(2003) found HIV-1 co-receptor expression on two-week-cultured NHOECs, while our flow cytometric analyses did not reveal CD4, CCR5, CXCR4, or galactosylceramide expression on three- to four-day-cultured NHOECs.
hBD-2 and -3 inhibit HIV-1 replication without being cytotoxic to immunocompetent cells
Pre-incubation of HIV-1 (X4 and R5 strains) with respective hBDs (recombinant forms generated in the Weinberg laboratory; see Quiñones-Mateu et al. [2003] for details) at concentrations ranging from 5 µg/mL to 40 µg/mL, followed by exposure of GHOST X4/R5 cells (osteosarcoma cells co-transfected with the HIV-2 long-terminal repeat driving expression of the green fluorescent protein {hGFP}), demonstrated that hBD-2 and hBD-3 were preferentially able to inhibit X4 virus from infecting the GHOST cells, but not hBD-1 (Fig. 2B). Moreover, reduced GFP fluorescence coincided with reduced viral reverse-transcriptase activity (Fig. 2C). Moreover, conditions that mimic the oral mucosal interface, low salt and no serum (Mandel, 1972), were found to elicit the best in vitro protection by the hBDs (Quiñones-Mateu et al., 2003). Interestingly, the concentration range of the hBDs that were used fell well within the reported concentrations of hBD-2 in normal oral epithelium (Sawaki et al., 2002). A thaizolyl-blue-based colorimetric assay (MTT method) (Pauwels et al., 1988) revealed no cytotoxicity against any of the immunocompetent cells that were used in the study, even at the highest hBD concentrations that demonstrated anti-HIV-1 activity.
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). In the case of hBD-3, this down-regulation was maintained for at least 24 hrs. Interestingly, hBD modulation of CXCR4 occurred even in the presence of high salt concentrations, suggesting that the hBD activity could be occurring on cells deeper in the mucosal epithelium. Finally, immunoelectron microscopy confirmed hBD localization to the cell membrane (Fig. 4).
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). Electrostatic interactions with virion-specific membrane structures, such as gp120, are plausible. Polyanionic compounds exert their anti-HIV-1 activity by binding to the positively charged sites in the V3 loop of gp120 (Schols et al., 1990; Witvrouw et al., 1994). Like other polycationic peptides which block infection with X4 HIV-1 isolates (e.g., T22, T134, and ALX40-4C) (De Clercq, 2002), the direct anti-retroviral effects of beta-defensins might be predicted to be very different, perhaps interacting with other viral surface domains. Theta-defensins have been shown to inhibit HIV-1 replication in vitro by binding to envelope sugar residues (Wang et al., 2003). Whether hBD2 and -3 exhibit lectin-like properties remains to be seen.
Significance
More than any other single development, the advances in HIV/AIDS therapeutics have caused a decrease in both AIDS incidence and death in the US and Europe. Despite these gratifying advances, the worldwide incidence of HIV infection is rising, and strategies to prevent the acquisition of HIV infection are urgently needed (Little et al., 2002). The discovery, in the mid-1990s, of the major HIV-1 co-receptors (Cocchi et al., 1995) has led to rapid development of novel antiretroviral strategies that target binding of HIV to these co-receptors. Moreover, observations of intrinsic resistance to the acquisition of HIV infection have demonstrated that failure of CCR5 expression is associated with high-level resistance to HIV infection (Dean et al., 1996; Liu et al., 1996). Nonetheless, studies in several cohorts of high-risk seronegative individuals have clearly demonstrated that the 32-base-pair mutation in the CCR5 open-reading frame, which results in the failure of surface expression of this chemokine receptor, is found at best in only a minority of high-risk HIV-seronegative individuals (Kokkotou et al., 1998; Kaul et al., 2000; Salkowitz et al., 2001). Thus, it is likely that other mechanisms determine risk for the acquisition of HIV infection in these groups. We propose that studies of the oral cavity may provide insights into intrinsic mechanisms of resistance to HIV infection. New drugs in development target different steps in the viral life cycle (Jacobson et al., 2000), gp 120-binding to the chemokine receptors CCR5 or CXCR4 (Cocchi et al., 1995), and the fusion of the viral and cellular membranes (Kilby et al., 1998). The fact that the oral cavity is naturally resistant to HIV-1 infection prompts us to ask how and why? While salivary components have been identified and are continuing to be studied as potential antiretroviral agents, we believe that there is much to be learned, and potentially tapped, from the oral mucosal epithelium. There is new, exciting information emanating from leading laboratories that defensin molecules may be a new frontier for studying the host’s defense against HIV-1 (Yang et al., 1999; Biragyn et al., 2002a,b; Zhang et al., 2002). Our preliminary studies suggest that an intriguing dynamic is occurring between the human oral epithelial cell and HIV-1 virions, possibly leading to mucosal protection through ß-defensin expression. We hypothesize that ’turning on’ inducible beta-defensins, locally, could result in less viral transmission through the mucosal barrier. Moreover, other epithelial-cell-derived antimicrobial agents may be induced along with the hBDs, upon HIV-1 challenge, and could then act collectively in protecting the oral cavity from HIV-1 infection. This may include such agents as SLPI, whose mechanism for selectively inhibiting R5 virus was recently elucidated (Ma et al., 2004). Results presented herein are intended to shed light on the properties of the oral mucosa that could contribute to its relative resistance to HIV-1, which could then be translated into promoting similar protection in more vulnerable mucosal barriers.
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Acknowledgments |
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