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Adv Dent Res 19:29-35, April, 2006
© 2006 SAGE Publications

The Effects of HIV Infection on Oral Mucosal Immunity

Presented at the Fifth World Workshop on Oral Health and Disease in AIDS, Phuket, Thailand, July 6–9, 2004, sponsored by Prince of Songkla University, Thailand, the International Association for Dental Research, the World Health Organization, the NIDCR/National Institutes of Health, USA, and the University of California-San Francisco Oral AIDS Center.

S.J. Challacombe* and J.R. Naglik

Department of Oral Medicine, Pathology and Immunology, Guys, Kings & St Thomas’ Dental Institute, King’s College London, Floor 28, Guys Tower, Guys Hospital, London SE1 9RT, UK

Correspondence: * corresponding author, Stephen.Challacombe{at}kcl.ac.uk


   Abstract
TOP
 Abstract
Introduction
 What Normally Protects the...
 What are the Consequences...
 HIV and Oral Epithelial...
 Conclusions
 References
 
Oral mucosal infections, especially candidiasis, are a feature of HIV disease, suggesting that compromised mucosal immunity within the oral cavity is a consequence of the viral infection. However, how this mucosal immunity is compromised and at what stage of HIV infection this occurs are unclear. Better understanding of the protection of the oral cavity against infection has allowed us to gain some insight into the local consequences of HIV infection. From a humoral perpective, IgA2 subclasses are reduced in HIV infection in saliva, and total secretory IgA levels are reduced in later disease. Similarly, mucosal antibody responses appear near normal in early HIV infection but reduced in AIDS. There is now convincing evidence that salivary IgA can be neutralizing to HIV 1 and HIV 2, as well as block epithelial transmigration. Oral cellular immunity is also affected by HIV infection. Transmission of HIV from one oral cell type to another appears to be confirmed by work showing that HIV can bind to or infect epithelial cells, Langerhans cells, and other mucosal cells. CXCR4 tropic (via GalCer and CXCR4) and dual tropic HIV strains have been shown to be able to infect normal human oral keratinocytes (NHOKs), and infectious HIV virions can also be conveyed from NHOKs to activated peripheral blood lymphocytes, suggesting a potential role of oral epithelial cells in the transmission of HIV infection. There is evidence of up-regulation of various receptors, including HIV receptors, on the surface of oral epithelium, and the epithelium may become more permeable. HIV may exploit this antigen uptake mechanism to cross epithelial barriers during co-infection with damage-inducing pathogens such as Candida. Immune responsiveness to many of the co-pathogens associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR), and recognition of a single pathogen can involve activation of multiple TLRs. Consequently, TLR-pathogen interactions could play an indirect but major role in regulating HIV-associated disease in the oral cavity. Thus, HIV infection appears to have both direct and indirect effects on oral mucosal immunity, affecting both cellular and humoral immunity as well as both specific and innate immunity.

Key Words: Mucosal immunity • oral • epithelial cells • salivary IgA • HIV


   Introduction
TOP
 Abstract
 Introduction
What Normally Protects the...
 What are the Consequences...
 HIV and Oral Epithelial...
 Conclusions
 References
 
Oral mucosal infections are recognized as a serious complication of HIV infection. Many viruses, bacteria, fungi, and parasites can colonize mucosal surfaces subsequent to the development of HIV infection. Although HIV infection leads to gradual diminution of systemic immunity, mucosal infections often occur at a time of normal or near-normal CD4 counts. Two key questions, therefore, are:

  1. What protects the oral cavity normally against HIV and other viral infections? and
  2. What are the consequences of HIV infection on oral cavity immunity?

The oral cavity is a part of the mucosal immune system and also has unique epithelia, tissues, bacteria, and diseases that are different from those of other mucosal sites. Both systemic and mucosal immune systems seem to play a role in defense, and these are both adaptive or innate and cellular or secretory. Innate defense mechanisms include defensins, Toll-like receptors, and cytokines produced by epithelial cells perhaps dependent on interaction with Toll-like receptors and various salivary factors, including mucins, histatins, salivary leukocyte protease inhibitor (SLPI), and lactoferrin. Secretory IgA is the main immunoglobulin of specific immunity in mucosae, whereas systemic immunity is mainly represented by cellular factors in the epithelium.

The increase in oral mucosal infections clearly suggests that HIV infection may have direct effects on the secretory immune system, and specific questions relate to how this mucosal immunity is compromised: (a) Are secretory IgA levels diminished? (b) Are the IgA subclasses perturbed, or is the avidity of mucosal antibodies significantly changed? (c) Is there evidence that non-specific innate factors in saliva are diminished? (d) Is there alteration of epithelial integrity, or are the keratino-cytokine networks impaired? (e) Can HIV directly infect oral epithelial cells? (f) What effect does concurrent infection with co-pathogens have on HIV infection? This review attempts to answer some of those questions.


   What Normally Protects the Oral Cavity against HIV and Other Viral Infections?
TOP
 Abstract
 Introduction
 What Normally Protects the...
What are the Consequences...
 HIV and Oral Epithelial...
 Conclusions
 References
 
HIV receptors and entry into host immune cells
Although most HIV-1 cases worldwide are transmitted through mucosal surfaces, their transmission through oral mucosa is thought to be uncommon (Rothenberg et al., 1998). The apparent rarity of transmission of HIV by the oral route suggests either that infective viral particles are absent or low, or that viral inhibitory factors are present and effective. The recovery rate of infectious HIV from saliva is low (1–2%) in HIV-seropositive individuals, although the DNA and RNA detection frequency of HIV by polymerase chain-reaction (PCR) is higher (20–50%) (Liuzzi et al., 1996). Mechanisms that might account for the low incidence of oral HIV transmission include neutralizing antibodies and innate anti-HIV inhibitory factors in saliva and/or epithelium (see below).

Entry of HIV-1 into host cells requires both the expression of the HIV receptor CD4+ and a co-receptor (‘entry receptors’; see Trkola, 2004). Several members of the chemokine receptor family have been shown to function as co-receptors for HIV entry (Pierson and Doms, 2003). The chemokine receptors CCR5 and CXCR4 are the principal receptors for macrophage-tropic and T-cell-tropic viruses, respectively, and are the most commonly used (Pierson and Doms, 2003). The viral envelope protein gp120 binds to entry receptors, but also binds to several other cell-surface molecules, including the dendritic-cell-expressed C-type lectin DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin) (van Kooyk and Geijtenbeek, 2003), the glycosphingolipid galactosyl-ceramide (GalCer) (Delezay et al., 1997; Alfsen and Bomsel, 2002), and proteoglycans such as syndecan-1 (Bobardt et al., 2003). These interactions do not lead to fusion and active entry into cells, but might protect bound virus from degradation by internalization, dissemination, or presentation to susceptible target cells (Bobardt et al., 2003; Trkola, 2004.

Immune cells in the oral cavity
The oral cavity has a full complement of immune cells, both intra-epithelially and submucosally, and these include cells bearing CD4 and CCR5 chemokine receptors. Intra-epithelial CD4 and CD8 cells can be found in uninflamed oral mucosa up to the permeability barrier, approximately one-third of the cell depth from the surface (Fig. 1Go). Intra-epithelial Langerhans cells are also present in relative abundance in normal oral buccal mucosa, and it is possible that the dendrites and numbers are up-regulated in inflammation such as lichen planus (Fig. 2Go). Thus, of three main receptors for HIV, DC-SIGN-positive cells, CD4- and CCR5-positive cells, T-cells, and macrophages are all present in the oral epithelium as well as the lamina propria. Langerhans cells are also CD4- and CCR5-positive, and the surface of the epithelium contains galactocyl-ceramide, also a receptor for HIV. One apparent difference of oral compared with vaginal epithelium is that in oral epithelium, Langerhans cells appear to reside only up to the lipid ridge layers, whereas in vaginal epithelium they reach the surface (Hussain and Lehner, 1995).


Figure 1
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  		Fig. 1 - Section of normal mildly inflamed oral mucosa showing the distribution of Langerhans cells (left x50, right x20). Note that the interdigitating processes appear to go around epithelial cells.

 

Figure 2
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  		Fig. 2 - CD4-positive cells within the epithelium in normal oral mucosa. Note that these are mainly intra-epithelial, with few cells in the connective tissue.

 
Toll-like receptors (TLR)
Toll-like receptors (TLRs) are the major innate recognition system of epithelial cells for microbial invaders in vertebrates (Beutler et al., 2003; Takeda et al., 2003). TLRs are type 1 transmembrane proteins belonging to a protein family characterized by extracellular leucine-rich repeats (LRR) and an intracellular TLR/IL-1 receptor/plant resistance (TIR) domain (Medzhitov and Janeway, 2000). Ten TLR members are known to exist in humans. Importantly, the different TLRs are triggered by conserved molecular structures (pathogen-associated molecular patterns [PAMPs]) expressed by bacteria, viruses, and fungi. These PAMPs include lipid or lipoprotein moieties (i.e., LPS; recognized by TLR1, TLR2, TLR4, and TLR6) and by protein motifs (TLR4 and TLR5), as well as by nucleotide sequences (TLR3 and TLR9) (Beutler et al., 2003).

It had been thought that recognition of a pathogen was restricted to a single TLR, but it is becoming evident that recognition of a single pathogen can involve activation of multiple TLRs (Underhill, 2003). TLRs trigger a cascade of signaling events that lead to the transcription of many cytokine and chemokine genes involved in immune activation (Kopp and Medzhitov, 2003). These signals involve the recruitment of the adapter molecule myeloid differentiation factor 88 (MyD88) and, in certain cases, TIR domain-containing adapter-inducing IFN-β (TRIF), TRIF-related adapter molecule (TRAM), and TIR domain-containing adapter protein (TIRAP), followed by the binding of IL-1R-associated kinase (IRAK) family members and the activation of TRAF-6, ultimately leading to the activation of NF-{kappa}B and mitogen-activated protein (MAP) kinases (see Fig. 3; Takeda et al., 2003). Consequently, TLR-pathogen interactions could play an indirect but major role in regulating HIV-associated disease (see below)

Salivary innate inhibitory factors for HIV
Detailed analysis of these factors is beyond the scope of this review, but over a dozen factors that have anti-HIV activity have now been reported in saliva. It is not clear whether they all have activity in vivo. Factors include mucins, SLPI, lactoferrin, proline-rich proteins, and cystatins, as well as specific antiviral activity residing in secretory IgA. Gel filtration of whole saliva reveals significant HIV-inhibitory activity in four main areas representing molecular weights of 10 to 20 kilodaltons, 40 kilodaltons, 80 kilodaltons and 150 to 2000 kilodaltons (Table 1Go; Kasmi et al., 2005). In a comparative study of different bodily fluids, Kasmi et al. showed that whole saliva consistently had higher inhibitory activity compared with parotid saliva, and that inhibitory activity in submandibular/sublingual saliva was intermediate.


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  		TABLE 1 - Role of Mucosal Immunity in Prevention of HIV Transmission
 
Postulated roles of oral mucosal immunity in the prevention of HIV transmission (Table 2Go) are: (a) to block HIV entry and prevent mucosal contact; (b) to prevent the initial infection of target cells, by blocking either the attachment of virus to epithelial cells or the attachment of infected cells to epithelial cells; (c) to intercept virus during epithelial transport; (d) to neutralize the virus within the mucosae if it gains access; and (e) to eliminate locally infected cells by antibody-dependent cellular cytotoxicity (ADCC).


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  		TABLE 2 - Mean Levels of HIV-inhibitory Activity for Seven Different Mucosal Fluid Types (from Kazmi et al., 2006)
 
Mechanism of activity of IgA against HIV
Theoretically, mucosal IgA could act against HIV in several ways, including: direct neutralization of HIV, inhibition of HIV enzyme activity, inhibition of attachment of HIV to its epithelial or other cell receptors or, a more recent concept, inhibition of transepithelial movement of HIV. There is now evidence that salivary IgA (as well IgA from serum) can block epithelial transcytosis of HIV across epithelial cells. This activity appears to be HIV-1 clade-specific and also neutralizing (Devito et al., 2002). Interestingly, salivas from HIV-1-exposed but serum-negative subjects (i.e., sex workers and heterosexual HIV-negative partners of HIV-positive individuals) have been shown to have good neutralizing activity against a primary clade B isolate as well as isolates of clades A and D (Broliden et al., 2001). Although present at low levels, these IgA demonstrated cross-clade neutralizing activity and were able to inhibit HIV mucosal transcytosis, suggesting an important functional role in protection against HIV infection.

Some restriction of salivary IgA tropism to HIV was suggested by Wu et al.(2003). Mucosal transmission by HIV is usually by R5 viruses, and X4 variants have emerged usually in established infection. Wu et al.(2003) purified parotid IgA from ten subjects and showed that four out of ten neutralized the R5 but not the R4 variants. Activity appeared to be targeted on gp120 and gp160. Others have shown that the IgA in saliva will inhibit the interaction between gp120 and the soluble CD4 receptors in a proportion of HIV-1-infected patients. In particular, the peptides within the CD4-binding domains can be recognized by salivary IgA, and this would seem to suggest that these epitopes might be targeted in any mucosal vaccination in humans (Vincent et al., 2004). It has been shown that, in contrast to IgG, serum IgA inhibits via the recognition of region 582–588 in the alpha helix of gp41 (Clerici et al., 2002).

The question of which antigens are recognized by IgA has been addressed in several studies. With regard to HIV-2, Lizeng et al.(2003) showed that 28 of 29 samples recognized gp125, gp105, and gp36, and that, specifically, the peptide 644–658 of gp36 was identified. Interestingly, only 17 of the 29 were found to be neutralizing. In a later study, the same authors showed that serum IgA from HIV-exposed but not -infected subjects had potent HIV-2-neutralizing activity, and that this was directed against gp36 (Lizeng et al., 2004).


   What are the Consequences of HIV Infection on Oral Cavity Immunity?
TOP
 Abstract
 Introduction
 What Normally Protects the...
 What are the Consequences...
HIV and Oral Epithelial...
 Conclusions
 References
 
Transmission of HIV through human mucosal surfaces
Much progress has been made in recent years in the investigation of the interplay between HIV-1 and its host cells. Like all viruses, HIV depends heavily on host-cell factors that enable the virus to enter cells, manifest the infection, and produce progeny virions. The exploitation of cellular machinery by HIV has been studied intensively over the past few years. These interactions are complex and are not yet fully understood. Our understanding of oral HIV infection remains elementary, and we lack understanding of the fundamental mechanisms by which HIV directly and indirectly affects oral mucosal epithelium.

It is accepted that the principle mode of transmission of AIDS in humans is through exposure of mucosal surfaces to HIV and HIV-infected cells (Milman and Sharma, 1994; Janoff and Smith, 2001). Virus entry across any mucosal surface is facilitated when epithelial barriers are damaged, but studies of SIV transmission in monkeys revealed that free SIV could infect via oropharyngeal mucosa (Stahl-Hennig et al., 1999). The oral mucosa and tonsils, in addition to esophageal mucosa, are potential sites for viral infection upon non-traumatic oral exposure to SIV in macaques (Milush et al., 2004). Rapid dissemination of HIV following oral transmission was observed in this study and may reflect SIV transmission across other mucosal surfaces. The rapidity with which SIV, and probably HIV, spreads throughout the lymphatics from mucosa indicates a major obstacle for a vaccine-amnestic immune response to eliminate infected cells prior to dissemination (Milush et al., 2004). In contrast, information regarding the interactions of HIV or HIV-infected cells with epithelial surfaces of the human oral mucosa is limited and contradictory, and the exact cellular and molecular events involved in initial HIV entry and mucosal infection are still poorly understood.

Although HIV can use various strategies to infect the human host via mucosal surfaces, HIV transmission at any intact mucosal surface will involve common steps, including survival of HIV or HIV-infected cells in mucosal secretions, interaction of HIV or HIV-infected cells with epithelial cells, transport of virus across the epithelium, and initial infection of CD4+/chemokine receptor+ target cells in the submucosa (Janoff and Smith, 2001; Neutra et al., 2001). There are numerous potential target cells that oral epithelium shares with other mucosal epithelium (see Figs. 1Go, 2Go). Some studies have indicated that mucosal dendritic cells, macrophages, and/or T-cells are the first cells infected. For example, in stratified squamous epithelia, motile dendritic (or Langerhans) cells move into the small intracellular spaces and even to the outer limit of the epithelium, where they may ‘sample’ pathogens or antigens from the mucosal surface (Neutra et al., 2001). Although this has not been shown directly in oral epithelium, HIV may exploit this antigen uptake mechanism to cross epithelial barriers during co-infection with damage-inducing pathogens such as Candida, where innate immune cells, including PMNs and Langerhans cells, will be recruited to the site of tissue damage.

HIV infection of human oral epithelium
Limited data exist on the direct effect of HIV infection/contact on oral epithelial cells. The fundamental issue of whether oral epithelial cells can be infected with HIV remains debatable and has been addressed in only a few studies. In vitro studies have shown that oral epithelial cells do not express CD4, but instead express GalCer and also express HIV co-receptors CCR5 and/or CXCR4. While some have found no evident HIV infection in oral epithelial cells (Quiñones-Mateu et al., 2003), others have demonstrated that gingival epithelial cells were susceptible to CCR5 but not CXCR4 viral strains via cell-free CD4-independent infection, and that infected cells were able to release infectious virus (Moore et al., 2003). They also showed that primary epithelial cells isolated from adenoids were susceptible to both cell-free and cell-associated virus. Another report demonstrated that CXCR4-tropic (via GalCer and CXCR4) and dual-tropic HIV strains could infect normal human oral keratinocytes (NHOKs), and co-culture studies have showed that infectious HIV virions can also be conveyed from NHOKs to activated peripheral blood lymphocytes, suggesting a potential role of oral epithelial cells in the transmission of HIV infection (Liu et al., 2003). HIV-1 infection of two salivary gland epithelial cell lines with lab-adapted strains and primary isolates of HIV-1 has been reported (Moore et al., 2002). Although neither of these cell lines expressed surface CD4, both expressed the alternative epithelial receptor GalCer and the co-receptor CXCR4. The natural ligand for CXCR4 (CXCL12/SDF-1) was able to block infection of both cell lines, indicating that these receptors were utilized for entry into the epithelial cells (Chow et al., 2002).

An interesting finding is that ethanol, at concentrations of alcohol that are frequently imbibed, significantly increased HIV infection of primary oral epithelial cells in cell culture (Chen et al., 2004). This seems to apply to both R4 and R5 strains and is by a gp120 independent mechanism (Zheng et al., 2004). Infection of primary oral epithelial cells also appears to be markedly enhanced by factors in semen, of obvious clinical relevance (Acheampong et al., 2005). The infectivities of HIV-1 strains YU-2, ADA, and NL4-3 for these oral epithelial cells were dramatically increased by the addition of physiological concentrations of dNTPs, spermine, and spermidine. It was also observed that the recombinant, cell-free HIV-1 proteins Nef, Tat, and gp120 (R5) induced apoptosis in exposed primary oral keratinocytes, compared with the results seen with untreated cells, possibly via the Fas/FasL apoptotic pathway (Acheampong et al., 2005).

Although limited, these findings demonstrate that epithelial cells of the oral cavity can be productively infected with HIV-1 by cell-borne virus in the absence of CD4. The mechanism of infection seems to be predominantly via GalCer and the CXCR4 co-receptor, and not through CD4 or CCR5 receptors. In vitro studies suggest that initial HIV infection may occur very early after contact of the virus or virus-infected cells with the epithelial barrier. However, detection of this crucial event in vivo is technically extremely difficult.

Association of HIV with the co-pathogen Candida albicans
Co-infection with non-HIV pathogens has been postulated to be an important exogenous factor that influences the severity and rate of disease progression in HIV+ individuals, reducing survival and increasing the risk of HIV transmission (Quinn et al., 1987; Blanchard et al., 1997). The co-pathogens of HIV infection include viruses such as human herpesvirus-6 and -8 (HHV-6, HHV-8), herpes simplex virus-1 (HSV-1), Epstein-Barr virus (EBV), several protozoan parasites, bacteria including Mycobacterium tuberculosis (Goletti et al., 1996), and the yeast Candida albicans (Blanchard et al., 1997; Orenstein et al., 1997; Sweet, 1997).

C. albicans is the most common fungal pathogen of humans worldwide and accounts for more than 60% of all fungal infections. Immune suppression is the hallmark of HIV infection, a feature of which Candida takes full advantage. Accordingly, oral candidiasis is the most common mucosal manifestation of HIV infection, and may occur in 50% of untreated HIV-infected subjects and 90% of AIDS patients (Phelan et al., 1987; Palmer et al., 1996). The severity and prevalence of oral candidiasis increase with advancing immune-suppression, making it an important predictive sign for the subsequent development of AIDS (Klein et al., 1984).

It is possible that both Candida and HIV may bind to the same cells and thus influence disease progression. It was recently shown that C. albicans is able to bind DC-SIGN in both DC-SIGN-transfected cell lines and in human monocyte-derived DC (Cambi et al., 2003). Moreover, in immature dendritic cells, DC-SIGN was able to internalize C. albicans in specific DC-SIGN-enriched vesicles, distinct from those containing the mannose receptor, the other known C. albicans receptor expressed by dendritic cells (Cambi et al., 2003). Together, these results demonstrate that DC-SIGN is an exquisite pathogen-uptake receptor that captures not only HIV (and other viruses) but also the important co-pathogen C. albicans.

Another intriguing observation is that HIV has been reported to bind directly to C. albicans cells, and lead to an increased production of known virulence factors of C. albicans (Gruber et al., 1998). Treatment of C. albicans with gp160, but not with gp120, led to an elevation of free and cell-bound aspartyl proteinase. In addition, culture supernatants obtained from C. albicans treated with gp160 or gp41, but not with gp120, showed a strong increase in proteinase activity. Why or how HIV gp160 or gp41, but not gp120, influences proteinase production, and whether they modulate Sap secretion directly or indirectly through another mechanism, remains to be elucidated. HIV infection might also promote C. albicans virulence in another way, since the HIV transactivating protein Tat binds RGD adhesin sequences present on the surface of C. albicans, to induce hyphal production (Gruber et al., 2001).

The patho-biological effects of HIV infection may directly induce changes in the candidal micro-environment and have been shown to contribute to the selection of different Candida strains with unusual phenotypes and genotypes (reviewed in Sweet, 1997). Together with impaired humoral or cell-mediated mucosal immunity and/or altered non-specific host defenses, these consequences of HIV infection are likely to contribute to the emergence of phenotypically and genotypically altered Candida strains (Challacombe et al., 1995) that possess altered or heightened virulence attributes (Ollert et al., 1995; Sweet et al., 1995a; De Bernardis et al., 1996).

Analysis of these data, together, suggests a dynamic interrelationship between HIV and C. albicans that could enhance either or both HIV and C. albicans infections in the oral cavity.

Salivary IgA, lactoferrin, and IgG
Salivary IgA and IgG subclasses have been examined in human subjects in HIV infection. Numerous authors have reported that salivary IgA2 is more profoundly suppressed than IgA1 in HIV infection (Sweet et al., 1995b; Challacombe and Sweet, 2002; Sistig et al., 2003), whereas, in AIDS patients, all IgA appears to be reduced, presumably reflecting increased immunodeficiency.

In addition to salivary IgA, other salivary factors may be altered in HIV infection. Thus, Bard et al.(2002) showed that whole salivary lactoferrin levels were increased. However, since whole saliva was used, it was not clear whether the increase might have been due to increased numbers of polymorphonuclear leukocytes or to serum transudate. The same authors (Bard et al., 2002) also reported that IgG subclasses and monomeric IgA were increased in subjects who were HIV-positive. This finding was confirmed by Sistig et al.(2003). Analysis of these data suggests an increased presence of serum factors in whole saliva, though whether this was from inflammation in the oral cavity or might be subsequent to increased permeability of epithelium was not determined.

Langerhans cells
Some years ago, Daniels et al.(1987) reported that Langerhans cells in hairy leukoplakia were markedly reduced, and this led to the concept that there might be a direct effect of HIV on Langerhans cells. This has been an area of some dispute, since other authors have not been able to confirm these findings. An interesting study endorsing a relationship between EBV and Langerhans cells has recently been published by Walling et al.(2004). These authors showed that EBV infection does indeed lead to a decrease in Langerhans cells in hairy leukoplakia, and that this decrease was independent of HIV viral loads. They showed that treatment of EBV itself (independent of HIV) led to an increase in Langerhans cells, and that cessation of treatment of EBV and return of EBV led to a recurrent decline in Langerhans cells. This paper clearly suggests that concurrent infection with EBV in HIV-positive people leads to decline in Langerhans cells in the areas affected, and that the decline is due to the EBV rather than to HIV. These findings therefore broadly support and explain those of Daniels et al.(1987) in their earlier studies.

In spite of observations that EBV can directly relate to Langerhans cell numbers, there is also evidence that oral mucosal Langerhans cells can be targeted by HIV. Chou et al.(2000) reported a correlation between detectable HIV p17 protein and depletion of Langerhans cells, suggesting a more direct linkage between these two types of cells. Interestingly, conjugates of Langerhans cells and T-memory cells (CD45RO positive) were also detected in hairy leukoplakia.


   HIV and Oral Epithelial Cells
TOP
 Abstract
 Introduction
 What Normally Protects the...
 What are the Consequences...
 HIV and Oral Epithelial...
Conclusions
 References
 
Influence of co-pathogens on HIV expression: role of epithelial Toll-like receptors (TLR)
Immune responsiveness to many of the co-pathogens associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR), which are the major innate recognition system for microbial invaders in vertebrates (Beutler et al., 2003; Takeda et al., 2003) (see above). Cytokine-mediated induction of the HIV long terminal repeat (LTR) through NF-{kappa}B activation is thought to be a major mechanism by which concurrent infectious agents enhance proviral transcription (Toossi, 2003; Lawn, 2004). In addition to indirect cytokine-mediated HIV induction, the interaction of co-pathogen PAMPs with TLR may result in the MyD88-dependent activation of HIV transcription through NF-{kappa}B itself or MAP kinase-dependent AP-1 (Rohr et al., 2003). Analysis of data from several in vitro studies strongly supports a role for TLR ligands in HIV induction in different human cell lines, including monocyte/macrophages, T-cells, endothelial cells, and mast cells (reviewed in Bafica et al., 2004), but a role is yet to be formally demonstrated in oral epithelial cells. Indeed, none of the above mechanisms has been formally demonstrated to explain TLR-mediated immune activation in HIV-infected human cells.

Other effects of HIV on epithelial cells
Other indirect effects of HIV infection on oral epithelial cells have been reported. Thus, Alpha Defensin 1 was increased by ten-fold within inflamed gingivae in chronic periodontitis (Jotwani et al., 2004). The HIV receptors langerin, DC-SIGN, MR, and galactosyl ceramide were all raised. Co-receptors CCR5 and CXCR4 were also raised. Uninflamed gingivae have relatively few CCR5-positive cells and no CXCR4-positive cells (Jotwani et al., 2004). These observations suggest that inflamed oral tissue, such as that found in chronic periodontitis, might be particularly sensitive to transmission of HIV through gingivae in the oral cavity.

In addition to Alpha Defensin 1, human epithelial cell Beta Defensin 2 and Beta Defensin 3 have been shown to be induced by HIV infection of oral epithelial cell lines (Quiñones-Mateu et al., 2003). This might be of functional significance, since, in the same work, human epithelial BD2 and BD3 were shown to inhibit HIV 1 replication. The mechanism of action appears to be the direct interaction of these defensins with virions, leading to a modulation of the CXCR4 receptor (Quiñones-Mateu et al., 2003).

One effect of HIV infection is that epithelial cells could be more susceptible to infection by other pathogens (Hille et al., 2002). EBV infection of oral epithelial cells (Walling et al., 2001), resulting in hairy leukoplakia, is markedly increased in HIV infection. Whether this increased susceptibility is due to local epithelial effects of HIV or the systemic sequelae of immunosuppression remains unclear.

Thus, overriding questions resulting from the studies of HIV and oral epithelial cells can be answered at least partially. Can normal oral epithelial cells be infected by X4 viruses? Studies detailed above suggest that the answer is yes, that both X4 and dual-tropic HIV can infect oral epithelial cells, but that very little evidence of infection has been found with R5 strains. The mechanism of such infection of oral epithelial cells seems to be via the galactosyl ceramide receptor and the chemokine CXCR4 co-receptor, and not CD4 or CCR5 receptors.

It can now be assumed that epithelial cells could be involved directly in the transmission of HIV, since passage from oral epithelial cells to activated peripheral blood lymphocytes has been demonstrated (Liu et al., 2003). Work demonstrating productive HIV infection of cell lines from salivary glands has also been reported, and the cell lines are derived from salivary glands (Han et al., 2000). It was noted that the latter productive HIV infection could be blocked by anti-galactosyl ceramide, though not by an anti-CD4 antibody. Transmission of HIV from intestinal epithelial cells to CCR5+ cells has also been demonstrated (Meng et al., 2002), suggesting that a similar mechanism may be common to several epithelia.

Mucosal vaccination strategy
Worldwide, most HIV infection occurs across mucosal epithelial surfaces. Thus, effective immunity at mucosal sites remains a key objective in vaccination strategy against HIV. Salivary antibodies can be a useful maker of such immunity, as well as an indication of protection of the oral cavity. Mucosal vaccination with the objective of inducing IgA anti-HIV activity has been examined in a few studies. Thus, Albu et al.(2003) showed that intranasal vaccination in mice with IL12 and CTB, as TH2-inducing antigens linked to gp120, induced high levels of IgA antibodies in broncho-lavage and vaginal washes. They also demonstrated that these antibodies were neutralizing to HIV. Similarly, Marinaro et al.(2003) showed that intranasal immunization with HIV tat protein gave secretory IgA antibodies in vaginal and intestinal fluids as well as the development of cytotoxic T-lymphocytes which resulted in protection in the murine model. These studies appear to provide proof, in principle, that mucosal immunization can induce, at different mucosal surfaces, IgA antibodies that can have neutralizing activity. An alternative strategy being developed by several groups, but with little reported to date, is the use of HIV peptides to block the binding of gp120 to DC-SIGN, to CD4, to CCR5, and to GalCer.

A novel HIV-CCR5 receptor vaccine strategy in the control of mucosal SIV/HIV infection has been proposed and tested in macaques (Bogers et al., 2004). The objective was to develop a novel SIV-CCR5 receptor vaccine that would protect macaques from SHIV infection by the vaginal mucosal route. The rationale for this strategy was that those humans who express the homozygous delta32 CCR5 mutation have an associated up-regulation of CC chemokines and down-modulation of cell-surface expression of CCR5, and are protected against HIV infection. Vaginal challenge in macaques led to mucosal and serum antibodies, and also raised CD4 counts and protection. Such an immunization strategy, targeting both the virus and its CCR5 receptor, may serve as a novel strategy in the prevention of HIV transmission (Bogers et al., 2004; Bergmeier and Lehner, 2006).


   Conclusions
TOP
 Abstract
 Introduction
 What Normally Protects the...
 What are the Consequences...
 HIV and Oral Epithelial...
 Conclusions
References
 

  1. IgA2 subclasses are reduced in HIV infection in saliva, and total secretory IgA levels are reduced in later disease. This has possible implications in susceptibility to IgA1 protease-producing bacteria.
  2. Mucosal antibody responses nevertheless appear near normal in HIV infection, though possibly reduced in AIDS.
  3. Salivary IgA can be neutralizing to HIV-1 and HIV-2, and can block epithelial transmigration. In other words, salivary IgA can be functional against HIV.
  4. Transmission of HIV from one oral cell type to another appears to be confirmed by the work showing that HIV can bind to or infect epithelial cells, Langerhans cells, and other mucosal cells.
  5. Oral epithelium appears to be more permeable and perturbed by HIV infection. The exact mechanism is not known, though there is evidence of up-regulation of various receptors, including HIV receptors, on the surface.
  6. Both X4 and dual-tropic HIV strains can infect oral epithelial cell lines.
  7. Immune responsiveness to many of the co-pathogens associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR), present on oral epithelial cells.
  8. Recognition of a single pathogen such as Candida can involve activation of multiple TLRs. Consequently, TLR-pathogen interactions could play an indirect but major role in regulating HIV-associated disease in the oral cavity.
  9. Co-infection with non-HIV pathogens such as Candida may be an important exogenous factor that influences the severity and rate of disease progression in HIV+ individuals, increasing the risk of HIV transmission.
  10. HIV infection appears to have both direct and indirect effects on oral mucosal immunity, affecting both cellular and humoral immunity as well as both specific and innate immunity.


   References
TOP
 Abstract
 Introduction
 What Normally Protects the...
 What are the Consequences...
 HIV and Oral Epithelial...
 Conclusions
 References
 

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Advances in Dental Research, Vol. 19, No. 1, 29-35 (2006)
DOI: 10.1177/154407370601900107
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