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(B1) Candida and Mycotic Infections

M.M. Coogan^1,*, P.L. Fidel, Jr.², M.C. Komesu³, N. Maeda⁴, and L.P. Samaranayake⁵

¹ Division of Oral Microbiology, School of Dentistry, University of the Witwatersrand, Private Bag X6, Wits 2050, Johannesburg, South Africa
² Department of Microbiology, Immunology and Parasitology, Louisiana State University Medical Center, New Orleans, LA, USA
³ Department of Morphology, Stomatology and Physiology, Ribeirão Preto School of Dentistry, University of São Paulo, Brazil
⁴ Department of Oral and Maxillofacial Surgery, Tokyo, Japan; and
⁵ Oral Biosciences, Faculty of Dentistry, University of Hong Kong

Correspondence: ^* corresponding author, cooganm{at}dentistry.wits.ac.za

	Abstract

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Oral candidiasis (OC) is the most common mucosal manifestation of HIV infection. This workshop examined OC and other mycoses associated with HIV infection. Historically, blood CD4 cell numbers were the primary prognosticator for the development of OC. However, a study that statistically evaluated the predictive role of HIV viral load vs. CD4 cell counts revealed viral load to be a stronger predictor for OC. The role of biofilms and antifungal resistance in recalcitrant OC is unclear at present. In general, micro-organisms including yeasts in biofilms are more resistant to antifungals than their planktonic counterparts. When the remaining organisms are eliminated, the few resistant organisms may not be problematic, because they are present in low numbers. Unusual exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. These infections may be recurrent and recalcitrant to therapy, be present in multiple and uncommon sites, increase with the progression of HIV disease, and may play a role similar to that of the more common mycoses. Typing and subtyping of yeasts are probably not critical to the clinical management of candidiasis caused by Candida albicans and non-albicans strains, including C. dubliniensis, because it is responsive to antifungal therapy. C. glabrata is probably the only exception. The presence of oral thrush in infants younger than 6 months of age is associated with an increased post-natal transmission risk of HIV infection. Thus, perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.

KEY WORDS: Oral candidiasis • viral load • biofilms • exotic mycoses • Candida typing • HIV acquisition

	Introduction

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The main sequelae of HIV infection are frequent and persistent opportunistic infections, with oral candidiasis being the most common mucosal manifestation of HIV infection (Patton et al., 2002). Studies have shown that the CD4 count can be used as a predictor for oral candidiasis (Schuman et al., 1998; Greenspan et al., 2000). The question arises whether the viral load is a better marker for oral candidiasis than CD4 counts in the blood. The emergence of antifungal resistance is a chronic problem of great concern for clinicians managing fungal infections in HIV disease (Samaranayake et al., 2002a; Sanglard and Odds, 2002). What factors contribute to this resistance? Do non-albicans Candida species and other fungi isolated from HIV-positive patients, as well as the biofilm architecture of superficial Candida infections, contribute to antifungal resistance? Is there a high prevalence of these fungi, and is their identification important for clinical management? Participants of this workshop addressed these issues using the following questions:

	List of Questions

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Question 1: What is more important in the development of oral candidiasis in HIV-infected patients, low CD4 counts or high viral load?

Question 2: Can the development of oral candidiasis serve as a marker for the level of viral load?

Question 3: Do Candida biofilms play a role in the recalcitrance of oral candidiasis in HIV disease?

Question 4: How prevalent are exotic mycoses in HIV-infected patients in the developing world?

Question 5: Are typing and subtyping of Candida species important in clinical management?

Question 6: What is the effect of oral thrush on the post-natal acquisition of HIV?

	Questions 1 and 2

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What is more important in the development of oral candidiasis in HIV-infected patients, low CD4 counts or high viral load? Can the development of oral candidiasis serve as a marker for the level of viral load? (Paul L. Fidel, Jr.)
Historically, blood CD4 cells have been the hallmark predictor for oropharyngeal candidiasis (OPC) (Rabeneck et al., 1993; Nielsen et al., 1994; Schuman et al., 1998; Greenspan et al., 2000). In the 1990s, 400 cells/µL was considered the level under which OPC was predicted. In the 2000s, the lower limit has been reduced to 200 cells/µL. HIV⁺ smokers are said to acquire a premature OPC with a higher CD4 cell number of 500 cells/µL (Galai et al., 1997; Palacio et al., 1997; Schuman et al., 1998; Greenspan et al., 2000; Slavinsky et al., 2002). In subsequent studies, there have been other factors thought to be predictors for or against OPC, including highly active anti-retroviral therapy (HAART), i.v. drug use, high-risk sexual activity, local host defense mechanisms, and HIV viral load (Romagnoli et al., 1997; Leigh et al., 1998; Palella et al., 1998; Schuman et al., 1998; Steele et al., 2000; Greenspan et al., 2001, 2004; Myers et al., 2003; Lilly et al., 2004). In fact, viral load was considered in some analyses to be more important than CD4 cell number as a predictor of OPC (Greenspan et al., 2004) and/or inversely associated with CD4 cell number (Riva et al., 2003). But in reality, few studies have formally addressed the role or association of CD4 cells counts vs. HIV viral load in OPC, and if viral load was as good or a better marker for OPC, or vice versa.

For these questions to be answered more formally, a cohort of HIV⁺ persons with and without OPC was examined in-depth for predictive factors associated with OPC. The cohort consisted of 49 HIV⁺ persons, stratified by those with OPC (n = 20) and those without OPC (n = 29) enrolled through the HIV Outpatient Program at the Louisiana State University Health Services Center, New Orleans, LA, USA. Half of the cohort was on HAART. CD4 cell numbers and HIV viral load were available for each patient. Also available were data on i.v. drug use, smoking, and high-risk sexual activity. The demographics are provided in Table 1. A modern exploratory statistical approach was taken to determine the dominant predictive factors for OPC in the cohort. Of the factors evaluated, only CD4 and HIV viral load were significantly associated with OPC when a univariate analysis was applied. In evaluation of the strength of the association between CD4 cell number and viral load on the proportion of OPC by logistic regression, viral load had a stronger association with OPC than CD4 cell number, by both geometric means (p < 0.001 for viral load vs. p < 0.04 for CD4 cells) and log transformation (p < 0.0003 for viral load vs. p < 0.0016 for CD4 cells).

The results of the CART revealed that, at HIV viral loads below 36,000 copies/mL, the likelihood of OPC is low, with no confounding effects of CD4 cells. But at viral loads greater than 36,000 copies/mL, the likelihood of OPC increases substantially and, additionally, is affected by the CD4 cell number. Specifically, when the viral load is > 36,000 copies/mL and the CD4 cells are < 45 cells/µL, there was a 100% correct classification for an OPC⁺ condition. At CD4 cell numbers between 45 and 150 cells/µL, there was an 80% correct classification for an OPC^– condition. Finally, but unexpectedly, at CD4 cell numbers between 150 and 500 cells/µL, there was again a 100% correct classification for the OPC⁺ condition. This latter finding stresses the lack of statistical stability of the CD4 cell number compared with the viral load in predicting OPC. Thus, by these statistical analyses together, viral load has a stronger association to OPC than does CD4 cell number.

This may represent a significant alteration in what is used as the major predictor for OPC. While CD4 cell number has historically been the primary predictive factor, these statistical analyses suggest that high HIV viral load may be a more stable predictor of OPC. Thus, one would address question 1 such that viral load is more important in the development of oral candidiasis in HIV⁺ persons. However, it should not be inferred that high viral load is causative for OPC, only that it is associated with the development of OPC. There are many other factors, as stated earlier, that most likely play a role in the direct development of OPC, including CD4 T-cells, innate immunity, CD8 T-cells, alcohol or i.v. drug use, and possibly high-risk sexual behavior. There is the possibility, however, that HIV does play a strong role in the development of OPC. There is a clear association of HIV protease gene mutation patterns with OPC (Hickman et al., 2002) that supports a direct involvement of HIV in the presence of OPC. Regarding question 2, these sophisticated statistical analyses suggest that, indeed, the development of OPC can serve as a marker for the viral load that is > 36,000 copies/mL. It must be recognized, however, that this information is based on a small cohort of HIV-infected individuals, and that results may differ with a larger cohort, especially with the actual value of viral load identified. But this serves as a good example of the types of analyses that can be conducted, together with some general interpretations based on clear statistical evidence. In the end, analysis of these data shows that viral load can be a formidable predictor for OPC in the HIV-infected population, and also that OPC can serve as a predictive factor for blood HIV viral load. Certainly, additional studies will be needed and strongly encouraged to confirm these preliminary findings or to identify additional ranges of the predictive capacity of viral load and CD4 cells for OPC, or vice versa.

	Question 3

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Do Candida biofilms play a role in recalcitrance of oral candidiasis in HIV disease? (Lakshman P. Samaranayake)
A biofilm is a structured microbial community of cells enclosed in a matrix of extracellular polymeric substances (EPS), irreversibly attached to a substrate, displaying phenotypic features that vary from their planktonic or free-floating counterparts (Baillie and Douglas, 1998a; Costerton et al., 1999; Davey and O’Toole, 2000; Donlan, 2001; Donlan and Costerton, 2002). Most notably, biofilm-associated cells demonstrate resistance to antimicrobials (Baillie and Douglas, 2000; Chandra et al., 2001; Mah and O’Toole, 2001; Ramage et al., 2002; Mukherjee et al., 2003). Many studies are available that characterize bacterial biofilms (Costerton et al., 1999; Davey and O’Toole, 2000; Donlan, 2001; Mah and O’Toole, 2001; Donlan and Costerton, 2002). Recently, however, several investigators have attempted to characterize fungal biofilms, notably Candida (Lecciones et al., 1992; Baillie and Douglas, 1998a, 1999, 2000; Chandra et al., 2001; Ramage et al., 2001a, 2002; Bachmann et al., 2002; Kuhn et al., 2002a; Lewis et al., 2002; Mukherjee et al., 2003). These studies have gradually unraveled the nature of candidal biofilms. Thus, in the initial stages of candidal biofilm formation (adhesion phase), there are no complex structures, but rather a few layers of adherent cells in the budding-yeast phase of growth (Samaranayake and MacFarlane, 1981). With biofilm development and maturation, the yeast community starts to differentiate to various degrees (Hawser and Douglas, 1994; Chandra et al., 2001).

Interestingly, candidal biofilms have a complex architecture that is similar to that of bacterial biofilms. One structural feature of candidal biofilms is the presence of water channels, which are thought to develop as a result of the detachment of individual microcolonies from the biofilm matrix. Such structures permit waste disposal and nutrient influx into biofilms, so that even the deeply embedded yeast cells have access to nutrients and oxygen (Fig.; Ramage et al., 2001b). Our studies indicate that the water channel systems in candidal biofilms are much akin to those of bacterial biofilms (unpublished data).

View larger version (174K): [in this window] [in a new window]   Fig. - A 48-hour biofilm of Candida albicans on denture acrylic. Note the predominant hyphal elements and the water channels.

It is now known that candidal biofilms are notoriously difficult to eradicate, due to the biofilm-specific properties such as their enhanced resistance to antimicrobials (Kuhn et al., 2002b). Compared with the planktonic forms, C. albicans and C. parapsilosis biofilms have been found to show decreased susceptibility to a variety of antifungal agents (including fluconazole, nystatin, chlorhexidine, terbenafine, amphotericin B, and the triazoles voriconazole and ravuconazole), as determined by XTT₅₀ analyses, a colorimetric tetrazolium salt reduction assay (Kuhn et al., 2002b).

The mechanisms underlying resistance of candidal biofilms to antifungals are poorly understood. Several possible mechanisms have been postulated:

1. Extracellular polymeric substances may confer drug resistance by decelerating the ingress of antimicrobials to cells that are deeply embedded in the community, thus acting as a physical barrier, in addition to absorbing a significant proportion of the drugs, thereby helping to reduce the concentration of the drug that reaches cells in the biofilm (Baillie and Douglas, 1998b).
   
2. The constituent cells of the biofilms, especially those embedded in the deeper layers, show suppressed growth rates, and these may metabolize or absorb relatively small amounts of antimicrobials, thereby being more likely to survive when exposed to the drugs (Evans et al., 1990).
   
3. Biofilm cell differentiation and emergence of different phenotypes (e.g., through switching) may also lead to heterogeneous antifungal resistance of yeast cells within the biofilm community (Suci and Tyler, 2003). Thus, while some biofilm cells are killed, other progeny that are resistant to antifungals can survive and re-establish a new community.
   
4. In comparison with planktonic cells, cells in candidal biofilms can up-regulate the expression of some genes, conferring antifungal resistance (Chandra et al., 2001).
   
5. The environmental milieu of the deeper cells in the community may have been at a pH and redox potential that are not conducive to the activity of antifungals.
   

These mechanisms, either singly or in combination, may confer antifungal resistance on candidal biofilms that comprise, in particular, the pseudomembranous variant of candidiasis commonly seen in HIV disease, leading to recalcitrance of the disease.

It is well-known that HIV-infected individuals, compared with healthy controls, have an increased incidence of symptom-free oral C. albicans carriage and a heightened frequency of oral candidiasis (Samaranayake et al., 2002b). One possible reason for this may be the heightened biofilm-forming ability of Candida colonizing the oral cavities of HIV-infected individuals. However, from our data on candidal biofilms comparing a large group of isolates from healthy and diseased individuals, and using two independent assay techniques (the XTT and crystal violet assays), we could not demonstrate significant differences in putative biofilm-forming ability between the isolates recovered from HIV-infected and those recovered from HIV-free individuals (Jin et al., 2003). To some degree, this is in agreement with our earlier studies that reported comparable buccal epithelial cell (BEC) adherence of isolates from HIV-infected and healthy individuals (Tsang and Samaranayake, 1999).

There are other generic factors not discussed here that may explain the increased C. albicans carriage and the heightened frequency of oral candidiasis in HIV-infected individuals. The first, undoubtedly, is their compromised immune system, which may also lead to possible alterations in the quality of host mucosal cells, which offer variable receptivity and avidity to candidal cells (Tsang and Samaranayake, 1999). Second, the Candida population itself may show genetic shuffling and modify attributes other than biofilm-forming ability as a consequence of HIV infection (Samaranayake et al., 2001, 2003). It is highly likely that the latter contributory factors, acting in tandem with the unique environment within Candidal biofilms—especially leading to drug resistance—contribute to the recalcitrance of oral candidiasis in HIV disease. Thus, in the long term, an understanding of the mechanisms conferring Candida biofilm formation and its antifungal resistance should elucidate the therapy and prevention of recalcitrant candidal infections seen in many compromised population groups, including those with HIV disease.

	Question 4

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How prevalent are exotic mycoses in HIV-infected patients in the developing world? (Marilena C. Komesu)
Opportunistic fungi have emerged as important agents of morbidity and mortality in immunocompromised patients. Reports from Argentina, India, and Thailand showed that non-albicans candidiasis is found more often than C. albicans candidiasis in HIV-negative patients, whereas C. albicans candidiasis occurred more often in HIV-positive than HIV-negative patients in the United Kingdom and Malawi. Reports from Brazil varied, with two studies reporting a predominance of C. albicans candidiasis in HIV-negative subjects, while another found that non-albicans candidiasis was more common in HIV-positive patients (Table 2).

Histoplasma capsulatum is a soil fungus found in the northeastern and central USA, Latin America, India, and Australia. The incidence of histoplasmosis in the HIV-infected population varies from between 0.5% and 2.7% in non-endemic areas, up to 27% in endemic areas. This is similar to the incidence of antibody-positive sera in the general population (Kucharski et al., 2000). Although mycoses are considered geographically limited and would not occur in non-endemic regions, analysis of the data on histoplasmosis from the Ribeirão Preto study suggests that this mycosis is more prevalent in the endemic regions, but is found occasionally in non-endemic areas.

Paracoccidioidomycosis is a deep, systemic, and progressive mycosis caused by Paracoccidioides brasiliensis. It is common in Latin America, with most patients having pulmonary involvement. Oral lesions are common and characteristic. They occur as multiple ulcers presenting with a mulberry-like appearance (Sposto et al., 1993; Godoy and Reichert, 2003). In the state of São Paulo in Brazil, Botteon et al.(2002) found antigens to this fungus in the blood of 21% of rural and 0.9% urban patients with no clinical signs of the disease. In suburban Ribeirão Preto, Brazil, this mycosis occurred in 0.7% of HIV-infected patients. This was lower than the 0.9% observed in the urban population in Brazil (Botteon et al., 2002).

Fusarium, Acremonium, Paecilomyces, Trichophyton, and Trichoderma species are an emerging group of fungi which may cause respiratory, skin, and disseminated diseases in immunocompromised individuals—not specifically HIV-infected patients. These diseases may be clinically similar to other deep mycoses. Consequently, the differential diagnosis may be difficult, and treatment results may be disappointing (Walsh and Groll, 1999; Lohoue Petmy et al., 2004). Dermatophytosis, onychomycosis, and pityriasis versicolor occurred in 5.9% of HIV-infected patients in the Brazilian study. In the general population, the literature shows 0.01% with dermatophytosis and 4.2% with Tinea pedis (Ellabib et al., 2002; Falahati et al., 2003).

Penicilliosis, caused by Penicillium marneffei, presented as an orofacial manifestation of AIDS restricted to Thailand and the Far East (Nittayananta, 1999; Patton et al., 2002), whereas Aspergillosis, caused by Aspergillus fumigatus or Aspergillus flavus, is not common in HIV-infected patients, although the fungi may be present worldwide. The latter has been reported in 0.35% of patients in the USA and 0.1% of patients in the Ivory Coast. These figures are similar to the incidence in HIV-negative patients (Eholie et al., 1997; Holding et al., 2000).

Mycosis in immunocompromised patients is secondary, disseminated, and sometimes exacerbates diseases. Prophylactic antifungal therapy may not constitute appropriate management for exotic mycoses, because the micro-organisms may be ubiquitous and form part of the host microbiota. Furthermore, problems may be experience related to drug interactions (mainly Citochrome P450 3A4 metabolism), which may complicate treatment. HAART (highly active anti-retroviral therapy) has led to a decreased incidence of these infections, but there is growing evidence of an increase in the incidence of penicilliosis in Southeast Asia and cryptococcosis in sub-Saharan Africa (Ruhnke, 2004).

In conclusion, we have observed that exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. They may be present in multiple and sometimes uncommon sites, their frequency usually increases as HIV disease progresses, and infections may be recurrent and sometimes recalcitrant to therapy. These infections are opportunistic, and oral mucosal involvement is a consequence of the oral condition, associated with the characteristics of the infectious agent and related to the general immunological and nutritional status of the patient. Due to global differences in the presentation of the exotic mycoses in HIV-infected cohorts, it is important to understand the natural prevalence of these diseases and their characteristics in the uninfected general population.

	Question 5

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Are typing and subtyping for Candidaspecies important in clinical management? (Nobuko Maeda)
There is an increased incidence of fungal infections associated with an increase in the number of immunocompromised hosts in the population. Candidiasis is the most frequently encountered fungal infection, and Candida albicans is considered the most pathogenic species implicated in this infection (Sandhu et al., 1995). The use of molecular-based analysis in epidemiological studies has demonstrated the genetic and geographic diversity of C. albicans (Stevens et al., 1990; Clemons et al., 1997; McCullough et al., 1999, 2004). C. albicans can be subdivided into 4 genotypes—A, B, C, and D (McCullough et al., 1999)—based on differences in 25 S rRNA sequences. C. albicans genotype D, renamed C. dubliniensis in 1995, is phenotypically and genotypically close to C. albicans (Sullivan et al., 1995). The clinical significance of C. dubliniensis is still poorly understood. However, isolates of C. dubliniensis from HIV-positive and AIDS patients readily develop resistance to fluconazole in vitro (Moran et al., 1997) and produced higher levels of extracellular proteinase than C. albicans (McCullough et al., 1995). This suggests that C. dubliniensis is more virulent than C. albicans. However, Tamura et al.(2001) have indicated that C. dubliniensis may not be strongly associated with AIDS in Japan.

In 1990, an epidemiological study of C. albicans from several regions in the United States and the United Kingdom found that there was an association of Group A genotype with increased resistance to the antifungal flucytosine (Stevens et al., 1990). McCullough et al.(1999) also showed that flucytosine susceptibility of C. albicans genotype A was significantly lower than for either C. albicans genotype B or C. In addition, C. dubliniensis was significantly more susceptible to fluconazole than any of the C. albicans genotypes. We undertook a study to determine the distribution of C. albicans genotypes A, B, C, and C. dubliniensis in HIV-positive and -negative adults and elementary school pupils in Japan. Samples were obtained from healthy and HIV-infected adults in Tokyo and healthy adults from an isolated island in the prefectures of Okinawa, Nagano, Yamaguchi, and Niigata and from elementary school pupils from Tokyo and Okinawa. Biological characteristics, secreted aspartic proteinase activity (SAPs), and susceptibility to several antifungal agents were determined.

Table 4 shows the distribution of genotypes A, B, and C of C. albicans and C. dubliniensis. C. albicans genotype A was the predominant genotype isolated. Genotypes B and C occurred in approximately 6 to 37% of all subjects. C. dubliniensis was the dominant species in elementary school pupils in Okinawa, followed by C. albicans genotype A, whereas C. dubliniensis was not isolated from elementary school pupils living in Tokyo. When we compared the carriage rates of C. albicans and C. dubliniensis in HIV-positive and age-matched healthy adults, the same tendency was observed. C. albicans genotype A was the dominant genotype, followed by genotypes B and C. However, the prevalence of C. dubliniensis in HIV-positive patients was slightly higher than in healthy subjects. This suggests that C. dubliniensis is distributed randomly in Japanese people regardless of HIV infection. This species was more prevalent in the juveniles living in the isolated island of Okinawa than in any other prefectures.

Ever since the use of advanced molecular analyses for epidemiological studies of C. albicans and C. dubliniensis, and the discovery of the genetic and geographic diversity of these two species, there have been many questions about their biological characteristics. We have found that the distribution of C. albicans and C. dubliniensis differed in the five areas of Japan we studied. In addition, C. dubliniensis produced fewer SAPs than C. albicans and was hence less virulent. In contrast, reports in 1995 and 1997 showed that C. dubliniensis was more pathogenic than C. albicans (McCullough et al., 1995; Moran et al., 1997). Although the genotypic difference between C. albicans and C. dubliniensis is distinct, there is still controversy about their phenotypic differences. Further global studies with DNA typing methods are required to clarify their phenotypic differences, including their incidence and virulence. Once this information becomes available, typing and subtyping the species could become important in clinical management. Based on the results of our study, it is arguable, at present, whether typing or subtyping of Candida species is important for the clinical management of this infection.

	Question 6

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What is the effect of oral thrush on post-natal acquisition of HIV? (Maeve M. Coogan)
The question whether oral thrush affects the post-natal acquisition of HIV was addressed in a longitudinal study undertaken in Nairobi, Kenya (Embree et al., 2000). Mothers and their children were followed from the children’s birth for at least 2 years. Blood specimens were tested for HIV-1 by serology and the polymerase chain-reaction. Infant oral thrush at less than 6 months of age was independently associated with an increased post-natal transmission risk of HIV-1 infection. The authors concluded that perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.

	Conclusion and Suggestions for Future Research

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Discussion was lively, and participants came to the following conclusions: Viral load is the best predictor of OPC status. Micro-organisms associated with biofilm are more resistant to antifungal than planktonic forms. Unusual exotic mycoses are common in HIV-infected patients from the developing world. Typing and subtyping of yeasts are not critical to the management of oral candidiasis, and the presence of oral thrush in infants is associated with an increase in the transmission of HIV infection.

During the workshop, the following topics emerged as important areas for future research:

1. What is the predictive value of HIV viral load and oral candidiasis?
   
2. Do commensal bacteria influence the pathogenesis of oral candidiasis?
   
3. How do epithelial cells, Candida virulence, the normal flora, and the host response influence HIV infection?
   
4. What are the mechanisms of pathogenicity and virulence of Candida albicans in oral candidiasis. Is it altered in HIV infection?
   
5. How do Candida biofilms develop, and what is their role in pathogenicity and resistance to antifungal agents?
   
6. Do Candida and the other mycoses associated with HIV disease vary geographically?
   
7. How does post-natal transmission of HIV occur in infants with oral candidiasis? How can it be prevented?
   

	Acknowledgments

 
The work was supported by NIH grant R01 DE12178 (P.L.F.) from the National Institute of Dental and Craniofacial Research (NIDCR). Individuals to thank for their efforts in this work include D. Mercante, J.E. Leigh, and Elizabeth Lilly.

The work reported here by L.P.S. was supported by the competitive earmarked research grant of the Research Grant Council of Hong Kong, the Outstanding Researcher Award to LPS provided by the University of Hong Kong.

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