Oral innate immunity in HIV infection in HAART era

Abstract

Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces provide not only a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed.

Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection contributed to a global reduction of HIV-associated oral lesions. However, prolonged treatment by HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: 1) What are the roles of oral innate immunity in health and disease?, 2) What are the effects of HIV infection on oral innate immunity?, 3) What are the roles of oral innate immunity against other co-infections?, 4) What are the effects of HAART on oral innate immunity?, and 5) Is oral innate immunity enhanced by HAART?

Introduction

The innate immune system, also known as non-specific immunity, represents the foremost barrier to pathogenic challenge, and plays a key role in the immune system. Oral innate immunity is considered to be an important component in host defense and immune surveillance in the oral cavity (1). These defenses against pathogen invasion vary in the different oral micro-environments or domains represented by the oral mucosa, salivary gland and saliva, and the gingival crevice (2).

Human immunodeficiency virus (HIV) infection in humans was first described more than 30 years ago, but so far the acquired immunodeficiency syndrome (AIDS) epidemic still continues relatively unabated. The main mode of HIV transmission is through genital and rectal mucosae that have led to intensive study on mucosal immune responses to HIV. However, it has been rarely reported that HIV was transmitted through the oral mucosa. Oral innate immunity, as the first-line to protect mucosa against HIV infection, seems to play a key role in preventing the infection at mucosal surfaces.

Mucosal innate immune cells comprise a diverse group of cells including the professional antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages, which plays important roles in the induction and regulation of immune responses at mucosal surfaces. It is well accepted that there is a link between innate and adaptive immunity as a key DC function is antigen presentation to T lymphocytes, whereas macrophages are more important for direct effector functions such as microbe recognition and killing (3-5). These cell types are among the first to sense invading pathogens in peripheral tissues through pattern recognition receptors (PRRs) that recognize conserved molecular motifs of microbes. Due to differences in expression of PRRs and antigen exposure, DC and macrophage functions vary in different tissues (4). This phenomenon directs the induction of local and adaptive immune responses, both of which are thought critical to successful prevention of HIV mucosal infection.

Highly active antiretroviral therapy (HAART) is currently the most effective therapy of AIDS, and oral innate immunity appears to be modulated with use of HAART (6). Although HIV infection no longer means a death sentence for those who can afford treatment, several particular immune responses may be impaired in HIV-infected individuals as a result of chronic HIV infection and co-infections (7). So a better understanding of the roles of oral innate immunity in HIV infection in HAART era should lead to improved prevention of pathogenic infections in HIV infected individuals, and to the development of novel strategies for mucosal AIDS vaccine.

This review article addressed five key questions as shown below:

1. What are the roles of oral innate immunity in health and disease?

2. What are the effects of HIV infection on oral innate immunity?

3. What are the roles of oral innate immunity against other co-infections?

4. What are the effects of HAART on oral innate immunity?

5. Is oral innate immunity enhanced by HAART?

What are the roles of oral innate immunity in health and disease?

Oral innate immunity is an integral part of an extensive and specialized compartmentalized mucosa-associated lymphoid tissue (MALT) (8). It consists of secretory immunity of the salivary glands, innate immune factors in saliva, epithelial cells, epithelial cell-derived innate immune agents, innate immune cells including Langerhans cells (LCs), intraepithelial lymphocytes, tissue macrophages, commensal and endogenous pathogens (1, 9). Oral innate immunity usually maintains the health of the oral cavity through the innate defense mechanisms including defensins, Toll-like receptors (TLRs), cytokines produced by epithelial cells and various salivary factors, such as salivary leukocyte protease inhibitor (SLPI), lysozyme and lactoferrin, calprotectin, mucins, histatins, and secretory IgA (1). As barriers to infection, oral innate immunity plays an important role in maintaining oral health (2). When it is impaired either by local or systemic causes, various oral infections and malignancies may be developed (1).

The roles of salivary factors in oral innate immunity

Saliva secreted by three pairs of major salivary glands (parotid, submandibular and sublingual) and many of minor salivary glands, is a main component of oral innate immunity. Saliva keeps the mouth environment to be stable through two mechanisms: by flushing microorganisms from mucosal and tooth surfaces; and by containing numerous antimicrobial, antifungal, antiviral and immunoregulatory components, which are the major oral defense mechanism against infection (1, 10). Salivary cationic peptides and other salivary defense proteins, including lysozyme, bactericidal/permeability increasing protein (BPI), BPI-like and proteins of palate, lung and nasal epithelial clone family (PLUNC proteins), salivary amylase, cystatins, proline-rich proteins, mucins, peroxidases, statherin (and others), defense against all kinds of pathogenic infection and are primarily responsible for innate immunity in the oral cavity (10). The marked decline in concentration of several salivary components in HIV infection may contribute to oral opportunistic infection.

The roles of epithelial cells in oral innate immunity

Human epithelial cells lining mucosal surfaces of the oral cavity consist of stratified squamous epithelia (11), which are parts of the innate immunity. These cells provide not only a physical barrier but also a chemical barrier against adhesion and invasion of microbes. The physical barrier is composed of cell-cell junctions, closely adherent cells, and a complex and continuous differentiation pattern. The thickness of squamous epithelia restricts the passage of pathogens from the outer mucosal surface, across the basement membrane, into the connective tissues. The squamous epithelium is occasionally interspersed with resident immune cells, including LCs which are DCs expressing the cell surface receptor langerin (CD207) (12). As for the chemical barrier, epithelial cells produce antimicrobial peptides, including hBDs and SLPI, and cytokines, for the defenses against various infection. Both hBD-2 and hBD-3 are expressed in normal uninflamed gingival tissue (13), perhaps due to chronic exposure to specific oral commensal bacteria that promote hBD expression. With all the functions described above, oral innate immunity helps in keeping homeostasis in the oral cavity and maintaining oral health.

What are the effects of HIV infection on oral innate immunity?

HIV infection appears to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies (1). The infection may directly affect the oral epithelium, resulting in the alterations in the cell structure and function that impair the innate immunity and promote colonization and infection by commensal and pathogenic organisms (6, 14, 15). Thus, oral lesions in HIV- infected individuals have been firstly documented since 1981 in a cohort of young homosexual males presenting with Pneumocystis carinii pneumonia (PCP) and concurrent mucosal candidiasis (16). Other oral opportunistic infections in HIV-infected individuals were also described with high prevalence during the early years of the epidemic, including oral hairy leukoplakia (OHL), aphthous ulcers, cytomegalovirus-induced ulcers, angular cheilitis, Kaposi's sarcoma, oral warts and necrotizing periodontal conditions (17). This indicates that HIV infection impair not only the host systemic immunity but also the local innate immune defense.

The mechanisms how HIV infection affects the oral innate immunity are not well established. TLR-pathogen interactions could play an indirect role in regulating HIV through the activation of HIV long terminal repeat sequences by host transcription factors (18). A previous study reported that chronic HIV infection (CD4⁺ < 200 cells/mL) in the absence of HAART was associated with significantly increased expression of several TLRs (19). It has been shown that TLR-2 surface expression and viral production were increased in HIV-positive patients (20). In addition, TLR-2 and TLR-4 may signal recognition of most bacterial and fungal mucosal pathogens leading to production of proinflammatory cytokines (21). It has been proposed that cytokine-mediated induction of the HIV long terminal repeat through NF-κB activation may induce the viral expression as observed in co-infected individuals (22).

HIV infection and impairment in salivary innate immune defense

Salivary innate immune defense is impaired in HIV infection. A previous study reported that salivary function is altered in early stage of the infection (23). Dysfunction of the salivary glands in early HIV infection seems to be the effects of HIV on the host immunity. Reduced salivary flow rate has been reported in most HIV/AIDS cohorts (24-28), and HIV-infected individuals often complain of xerostomia (29, 30). In addition, many patients suffer with HIV-associated salivary gland disease (HIV-SGD) (31) such as Sjögren's-like syndrome with hyperglobulinemia along with diffuse and/or infiltrative lymphocytes within the salivary gland (32, 33).

Salivary composition is also changed in HIV infection (34). Whole salivary lactoferrin and total IgA levels were significantly higher in HIV-infected patients with oral candidiasis (OC) than those without the lesion and healthy subjects (42). A study by Muller et al (35) reported that lactoferrin and secretory IgA outputs of parotid glands were significantly decreased in HIV-infected individuals, and their combined deficiency may contribute to the frequent oral infections seen in those subjects (35). In addition, calprotectin levels, which were significantly increased in the presence of candidal carriage (36) was shown to be reduced in HIV-infected patients with either low or high salivary counts of Candida (36, 37). Previous studies reported increased levels of sodium and chloride in glandular saliva obtained from HIV-infected individuals (24-26). Changes in concentrations of the electrolytes in saliva may be clinically relevant because ionic strength can modify antimicrobial properties of several salivary proteins (38).

HIV infection and impairment of epithelial cell function in innate immunity

In recent years, several studies have focused on the investigation of the interplay between HIV and host cells (1, 39). Like all viruses, HIV depends mainly on host factors that enable the virus to enter the cells, manifest the infection, and produce progeny virions. Although the exploitation of cellular machinery by HIV has been studied in the past few years (1), the understanding of the fundamental mechanisms by which HIV directly and indirectly affect oral mucosal epithelium is still lacking.

Epithelial cell function in innate immunity may be impaired by HIV infection (40-42). as levels of SLPI expression in saliva appear to be altered in HIV-infected individuals (43). SLPI expression may be manipulated by HIV through infection-independent interactions initiated at the cell surface (44). Previous studies reported that the concentration of SLPI was increased in the presence of HIV infection (44-46). The significant increase in SLPI mRNA expression and protein secretion was dose and time dependent, occurred rapidly after virus contact, did not require productive cellular infection, and was elicited specifically by the external envelope glycoproteins of HIV strains (44). A recent study by Nittayananta et al. (43) reported that HIV infection may affect the expression of oral SLPI at both transcriptional and translational levels. The study showed that the expression of oral SLPI mRNA in HIV-infected individuals was increased; however, the levels of SLPI protein in stimulated saliva was decreased (43). This finding may indicate that the expression of SLPI is also controlled at the post-transcriptional level, and that HIV infection may alter message translation or interfere with the protein synthesis. In addition, the study reported that CD4 T-cell count and HIV viral load were the factors associated with the oral SLPI expression (43). Thus, HIV infection may impair the function of oral epithelial cells in innate immunity leading to the alterations of the expression of oral SLPI. As a consequence, various opportunistic infections and malignancies are observed in HIV-infected individuals (47-49).

Other indirect effects of HIV infection on the function of oral epithelial cells in mucosal innate immunity have also been reported (1). The expression of hBD-2 and hBD-3 has been shown to be induced by HIV infection of oral epithelial cell lines (50). A previous study by Nittayananta et al (6) reported that levels of hBD-2 protein in both unstimulated and stimulated saliva were significantly increased in HIV-infected patients compared to non-HIV individuals. This might be of functional significance as hBD-2 and hBD-3 were shown to inhibit HIV replication in vitro [49].

HIV infection and impairment in function of innate immune cells

Function of innate immune cells seems to be impaired in HIV infection. A previous study reported that innate immune cells such as LCs is reduced in HIV-infected individuals with OHL suggesting that HIV might have a direct effect on LCs (51). However, other study showed that Epstein-Barr virus (EBV) infection does indeed lead to a decrease in LCs in OHL, and that this decrease was independent of HIV viral loads (52). However, there is an evidence that oral mucosal LCs can be targeted by HIV (53). Meanwhile, a correlation between detectable HIV p17 protein and depletion of LCs has been reported, suggesting a more direct linkage between these innate immune cells and HIV infection (54). In addition to LCs, other innate immune cell function may be altered in HIV infection. The impairment in the function of innate immune cells resulting in low degree of phagocytosis by neutrophils, and monocytes may contribute to increased frequency and severity of bacterial and opportunistic infections in this population.

Effects of HIV-1 on oral innate immunity involved in periodontal disease is not clear. It has been shown that the innate immune system plays a significant role in this inflammtatory reaction as initial response to bacterial infection leading to the release of various cytokines and other mediators (55, 56). A variety of innate immune defense is induced by the colonization and invasion of tissue by periodontal pathogens in order to restore the balance with the resident oral microbiota. This process may lead to periodontal tissue damage and the destruction of alveolar bone.

Prostaglandin produced by monocytes, has been shown to involve in the pathogenesis of periodontal disease. It plays an important role as an inflammatory mediator in mucosal inflammation and host response. Although little is known about the role of prostaglandins in the etiology of periodontitis in HIV-infected patients, increased levels of this mediator in gingival fluid may represent an important biochemical predictor for the future progression of periodontitis (57). A previous study reported that high levels of PGE2 in subgingival sites might be a risk-factor for the progression of pre-existing periodontitis in HIV-infected patients (58). In addition, high levels of circulating PGE2 has been shown in AIDS patients, which may suppress the specific antigen response of both lymphocytes Th1 and Th2 (59).

What are the roles of oral innate immunity against other co-infections?

The relatively high prevalence of secondary co-infections in HIV-positive individuals implies that HIV induces a profound perturbation of the mucosa, particularly in the oral cavity (1). This may be due to direct effect of HIV on the oral epithelium. Alternatively, the infection by HIV may have both direct and indirect effects on oral innate immunity resulting in alterations that promote colonization and infection by commensal and pathogenic organisms. Co-pathogens resulting in opportunistic infection include fungus, bacteria, and virus such as human herpesvirus 6 and 8 (HHV-6, HHV-8), herpes simplex virus 1/2 (HSV-1/2), EBV, and human papilloma virus (HPV) (1, 60, 61).

Fungal infection

OC is the most common oral opportunistic infection in HIV-infected individuals, and associated with defective cell-mediated immune responses (62). C. albicans is the predominant cause of both superficial and invasive forms of OC (63). However, non-albicans Candida spp., such as C. glabrata, C. tropicalis, C. parapsilosis, C. guilliermondii, and C. krusei are also pathogenic to humans and have emerged as important opportunistic pathogens in the oral mucosa (64, 65). C. albicans interacts with epithelial cells in terms of adherence, invasion, and induction of cell damage.

The role of host oral innate immunity in the development of OC is not fully elucidated. Previous studies have shown that defensins, especially β-defensins have the capacity to kill or inactivate fungi in vitro (66-69). Recognition of C. albicans by the innate host defense system is mediated by PRRs from the TLR, C-type lectin-receptor (CLR), and NOD-like receptor (NLR) families (70, 71). These PRRs initiate an appropriate antimicrobial response to try to contain the infection, which involves the up-regulation of specific antimicrobial peptides including defensins. The second major task for the innate immune system is to activate an appropriate adaptive immune response against the invading organism (63). Thus, PRRs induce innate immune responses and also modulate cellular and humoral adaptive immunity during Candida infections (63, 72).

During oral infection with Candida, many cytokines are also secreted by oral epithelial cells, which maintain a central role in the protection against fungi. In general, pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNF, GM-CSF, and others) regulate leukocyte trafficking and/or activate a strong antifungal response by these cells (73, 74). A previous study by Netea et al. (75) demonstrated that C. albicans induces immunosuppression through TLR-2-derived signals that mediate increased IL-10 production and survival of Treg cells (75). This may represent a novel mechanism in the pathogenesis of fungal infections. In addition, oral epithelial cells are capable of inducing antimicrobial peptides, such as defensins, cathelicidins, and histatins which control Candida growth and infection (76). Among these peptides, hBD-2, hBD-3, LL-37 and histatin-5 (Hst-5) exhibit potent anti-candidal properties (77, 78). Considerable evidence has demonstrated a close association between defensins and TLRs, especially between β-defensins and extracellular TLRs (79). Although the antifungal activity of hBDs has been characterized to some extent, their exact role in the host defense mechanism against fungal infection remains unclear.

Viral infection

Considerable evidence has indicated that α-defensins can inhibit HIV and HSV infections in vitro (80). It has been known that HSV is susceptible to defensin action, especially θ-defensins (81). Thus, defensins with β-sheet structure have been gaining much interest because of their antiviral property. It has been reported that HD-5 and its mutants displayed affirmatory but differential anti-HSV-2 effects in vitro by inhibiting viral adhesion and entry (82).

HHV-8 is an identified virus etiologically associated with Kaposi's sarcoma (61, 83). It is present in saliva and the non-lesional oral mucosa (not simultaneously) of patients with impaired immunity, with or without HIV co-infection (84). The oral epithelium seems to represent an independent location of HHV-8 residency and may be of the viral replication. However, little is known about the oral innate immune factors that may play roles in regulating the viral infection. The clinical implications of HHV-8 residency in the oral epithelium need further clarification (84).

EBV, a double-stranded DNA virus in the Gamma herpesvirinae subfamily (85), is ubiquitous in the general human population (86, 87). OHL, a common oral manifestation of HIV-infected individuals (88), is claimed to occur by EBV infection of oral epithelial cells (89). However, it is still unclear whether the increased susceptibility to EBV is due to local epithelial effects of HIV infection or the systemic immunosuppression caused by the virus.

Of interest, individuals who are infected with HIV have greater risk for developing EBV-associated malignancy including non-Hodgkin's lymphoma (NHL) compared with that in the general population (47). However, the roles of oral innate immunity on pathogenesis of EBV-associated oral lesions in HIV-infected individuals are poorly understood and need further investigations (90-92).

HPVs are a group of 7.9 kb double-stranded circular DNA viruses that are involved in epithelial carcinogenesis and found in premalignant and malignant lesion (93). The prevalence and incidence of HPVs infection and HPVs-associated diseases including oral squamous cell carcinoma (OSCC) have been shown to be greater in HIV-infected subjects when compared to non-HIV individuals (60, 94). A previous study by Chuang et al. (95) reported that patients with HPV-16 positive surveillance salivary rinses are at high risk for development of recurrence and distant metastasis of head and neck squamous cell carcinoma (HNSCC). However, the roles of oral innate immunity on pathogenesis of HPV-associated oral malignancies in HIV-infected individuals are not well established.

Bacterial infection

It has been reported that deficiency of alpha-defensins is associated with the risk for invasive bacterial infections observed in AIDS patients (96). The antibacterial activity of defensins is generally ascribed to their ejects on microbial membranes. Defensin-like peptides, being positively charged, interact with negatively charged components of microbial membranes that include lipopolysaccharide (LPS) in Gram-negative bacteria, polysaccharides (teichoic acid) in Gram-positive bacteria, and phospholipids (phosphotidyl-glycerol) (97).

It is well established that periodontal disease is developed as a result of the interplay between subgingival microbiota and host response. However, in HIV-infected patients, the etiology of periodontal disease is not yet clear. Some studies reported no difference between the composition of subgingival microbiota of HIV-infected and non-HIV infected individuals (98, 99). However, other studies detected a greater prevalence of periodontal pathogens including A. actinomycetemcomitans, Porphylomonas. gingivalis, Prevotella intermedia, and Fusobacterium nucleatum, as well as a combination of these species in HIV-infected patients compared to non HIV-infected individual (99-103). P. gingivalis has been shown to play roles for the increase of invasion and HIV infection in oral epithelial cells in vitro (104, 105). In addition, it induced the re-activation of latent HIV which is found as provirus in genomic host cells. P. gingivalis and other species of oral bacteria and their components in DCs and epithelial cells can trigger the viral re-activation (106). This may suggest that periodontal disease is a risk factor for the reactivation of the virus, which may lead to its dissemination among the infected individuals (107, 108).

What are the effects of HAART on oral innate immunity?

HAART is the standard treatment of HIV infection, which consists of a combination of three or four drug groups including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), and fusion inhibitors (FIs) (109). The introduction of HAART has changed the scenario of HIV infection and resulted in a dramatic reduction in morbidity and mortality by achieving maximal viral load suppression and increasing CD4⁺ T cell counts. Many studies have demonstrated a significant reduction of AIDS-related complications, especially oral lesions, from pre-HAART to the HAART era (110). OC is the most common opportunistic infection of HIV-infected individual (111), but its incidence declined dramatically among those on HAART (112-114).

HAART may alter oral innate immune defense. The functions of both monocytes and of neutrophils among patients with HAART have been shown to be enhanced (115). Thus, effective management of HIV infection by HAART, reflected by the absolute CD4 T cell count and the viral load, may improve the function of phagocytosis and oxidative burst (115, 116) as well as functional improvement of neutrophils and monocytes against C. albicans among the infected individuals.

A recent study by Nittayananta et al (49) revealed that HAART significantly decreased salivary flow rates of HIV-infected patients. The salivary component has also been shown to be different between those with HAART and without HAART (34). In addition, the expression of oral SLPI has been shown to be affected by the use of HAART (43). A study by Nittayananta et al. (43) reported that the levels of SLPI protein in stimulated saliva was decreased in those on short-term HAART compared with those who did not take the medications. However, the expression of SLPI mRNA did not change significantly (43). The findings may indicate that the expression of SLPI is also controlled at the post-transcriptional level, and that HAART may alter message translation or interfere with the protein synthesis (43). However, there was a study reported that the concentration of SLPI is increased in patients on HAART (45). Many factors may contribution to the differences between the studies such as sample size and cohort effects, as well as types of saliva studied (whole saliva vs. glandular saliva). The levels of hBD-2 proteins in stimulated saliva were also found to be significantly different between HIV-infected patients who received HAART compared to those who were not on the medication (6). These findings suggest that HAART may impair oral epithelial cells functions in innate immunity leading to the alterations of the oral hBD-2 expression (6). Although previous studies suggested that oral innate immunity is affected by the use of HAART (6, 43, 115), knowledge about the mechanisms involved is still lacking and needs further investigations.

Is oral innate immunity enhanced by HAART?

It is not clear whether oral innate immunity is enhanced by HAART. The levels of LCs in the gingival epithelium have been shown to be reduced in HIV-infected individuals when compared to non HIV-infected subjects.(117). However, greater number of LCs has been noted in HIV-infected patients with moderate chronic periodontitis undergoing HAART compared to non HIV-infected individuals (118).

A previous study reported that protease inhibitors have been associated with xerostomia (119). In addition, both unstimulated and stimulated salivary flow rates of HIV-infected individuals with HAART were significantly lower than that of those without HAART (49). Thus, prevalence of oral Candida carriage is expected to be high among this population. In addition, a decrease in salivary flow rates may increase the risk of oral opportunistic infection. Oral Candida carriage has been shown to correlate with the presence of oral epithelial dysplasia (120). Chronic infection by Candida may cause malignant transformation resulting in the development of OSCC (121). Because HIV-infected individuals receive HAART as a life-long therapy, this group of subjects may be susceptible to chronic candidal infection that could potentially lead to malignant transformation. Thus, those who were on long-term use of HAART had a greater risk of developing oral lesions than those with short-term HAART (49).

When observed changes in the levels of hBD-2 proteins in stimulated saliva with the use of HAART, Nittayananta et al. (6) found that the levels of hBD-2 protein in stimulated saliva seemed to be increased with short-term use of HAART, but decreased with long-term use of the medication (6). In addition, the levels of SLPI proteins in stimulated saliva were decreased with the use of HAART (43). These finding suggests that oral innate immunity may be enhanced by short-term use of HAART, but it may be adversely affected by long-term use of the medication (6). However, no significant association between types of HAART and the levels of salivary hBD-2 proteins was observed in the study because most patients received the same regimen of 2 NRTIs + 1 NNRTI. It should be noted that AZT may incorporated into DNA causing gene mutations, and has genotoxic effects leading to genomic instability in cultured cells (122). Thus, prolonged treatment by this medication potentially causes malignant transformation of oral epithelia (122).These genetic changes have been used to predict the risk of malignant transformation of oral epithelial cells (123).

In conclusion, oral innate immunity plays important roles in maintaining oral health, and defending against commensal and pathogenic infections in the oral cavity. This oral innate immune defense is affected by HIV and other co-infections leading to changes in the components of oral innate immunity. In addition, oral innate immunity seems to be altered by the use of HAART. With the short introduction of HAART, oral innate immunity is enhanced. However, the long-term use of HAART may cause adverse consequences on mucosal innate immunity, which may increase the risks of infection and malignant transformation of the oral epithelia. Mechanisms involved in the interplay between HIV and other co-pathogens with the host innate immune responses are not well established and need to be further studied.