Share this article on:

Candida and candidiasis in HIV-infected patients: where commensalism, opportunistic behavior and frank pathogenicity lose their borders

Cassone, Antonioa; Cauda, Robertob

doi: 10.1097/QAD.0b013e3283536ba8
Editorial Review

In this era of efficacious antiretroviral therapy and consequent immune reconstitution, oropharyngeal and esophageal candidiasis (OPC and OEC) still remain two clinically relevant presentations in the global HIV setting. Both diseases are predominantly caused by Candida albicans, a polymorphic fungus which is a commensal microbe in the healthy individual but can become an aggressive pathogen in a debilitated host. Actually, C. albicans commensalism is not the result of a benign behavior of one of the many components of human microbiota, but rather the result of host's potent innate and adaptive immune responses that restrict the growth of a potentially dangerous microrganism on the epithelia. An important asset guarding against the fungus is the Th17 functional subset of T helper cells. The selective loss of these cells with the progression of HIV infection causes the decay of fungal containment on the oral epithelium and allows C. albicans to express its pathogenic potential. An important part of this potential is represented by mechanisms to evade host immunity and enhance inflammation and immunoactivation. In C. albicans, these mechanisms are mostly incorporated into and expressed by characteristic morphogenic transitions such as the yeast-to-hyphal growth and the white-to-opaque switch. In addition, HIV infection generates an ‘environment’ selecting for overexpression of the virulence potential by the fungus, particularly concerning the secreted aspartyl proteinases (Saps). These enzymes can degrade critical host defense components such as complement and epithelial defensive proteins such as histatin-5 and E-cadherin. It appears that part of this enhanced Candida virulence could be induced by the binding of the fungus to HIV and/or induced by HIV proteins such as GP160 and tat. Both OPC and OEC can be controlled by old and new antimycotics, but in the absence of host collaboration, anticandidal therapy may become ineffective in the long run. For these reasons, new therapeutics targeting virulence factors and specific immune interventions are being addressed. Among these new approaches, vaccination is a promising one. Two subunit vaccines based on antigens dominantly expressed by C. albicans in vivo, that is the Als3 adhesin and Sap2, have recently undergone phase 1 clinical trials. Overall, studies of Candida and candidiasis in the HIV-positive patient while certainly contributing to a more effective control of the microorganism may also provide useful information on HIV–host relationship itself that can assist the fight against the virus.

aDepartment of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità

bDepartment of Clinical Infectious Diseases, Catholic University of Rome, Rome, Italy.

Correspondence to Antonio Cassone, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Tel: +39 03408607256; fax: +39 049902813; e-mail:

Received 23 February, 2012

Accepted 7 March, 2012

Back to Top | Article Outline


Since the report by Klein et al. in 1984 [1], oropharyngeal candidiasis (OPC) has represented a landmark feature of HIV infection. One of AIDS-defining illnesses is esophageal candidiasis (OEC), which usually occurs at CD4+ cell count less than 200 cells/μl [2]. The incidence of OPC has markedly declined in the current era of antiretroviral therapy (ART) and immunoreconstitution of HIV-depleted host immunity [3–7], but remains frequent in several population groups. This includes individuals with difficult access to ART or with failure in immunologic response and resistance to HIV drugs. The persistent threat of mucosal candidiasis as an important medical presentation in the setting of HIV individual is shown by both epidemiologic surveys and anatomical records, as well as by the high rate of persistent oral colonization by Candida in individuals under ART [8–15]. This persistence is associated with a widening spectrum of causative Candida species and increasing antimycotic resistance that seriously threatens the efficacy of anticandidal drugs [16–19]. Probably for these reasons, in some HIV-positive cohorts, OEC incidence in the ART era has been reported to be substantially equal to that of pre-ART [12]. With all evidence, OPC and OEC have not ended in the ART era [7].

The aim of this review is not a recapitulation or a reinterpretation of the literature on candidiasis in the HIV-positive individual; excellent reviews have already been published on this subject [8,9,11,19,20]. We will rather address some peculiar and, to some extent, intriguing events which characterize Candida behavior in the HIV infection setting. We will focus upon disease mechanisms and interactions between two pathogens, Candida and HIV. They are so distant taxonomically, but, in a way, both are capable of determining a very special relationship with the human host, and still more, capable of cooperating for disease onset and progression.

Back to Top | Article Outline

The disease

OPC with its various clinical presentations (Table 1) used to be the most common manifestation of mucosal infection in HIV-positive individuals. Up to 50% of untreated individuals and 90% of AIDS patients had OPC, depending on the cohort examined and stage of HIV infection. In turn, OEC could be present in as nearly as 70% of individuals with OPC. Of interest, neither chronic, recurrent vaginal infection nor candidemia or deep-seated candidiasis is a distinctive feature of HIV-infected individuals. However, HIV-positive individuals with neutropenia, or deep surgery, or bearing permanent central venous catheter could be affected by invasive candidiasis. These differences reflect the markedly different risk factors for these very distinct syndromes, the well recognized anatomical and physiological differences, as well as the compartmentalization of antimicrobial host defenses [20–25] (Table 2). Together with pneumocystosis and Kaposi sarcoma, OEC is also a relatively frequent opportunistic infection in the so-called paradoxical immune reconstitution inflammatory syndrome IRS which follows initiation of ART [26]. Finally, OPC is a distinctive clinical presentation of chronic mucocutaneous candidiasis, which also includes recurrent or persistent skin, nails and genital infection by Candida. Recent data strongly suggest that CMC is due to inherited defective production of IL-17, which has also been involved in the determination of OPC in the HIV-positive individuals ([27]; see below).

Back to Top | Article Outline

The pathogen

Various species of Candida can cause OPC and OEC, but in most surveys, Candida albicans largely outnumbers the other yeast species, and this review will essentially be limited to this fungus. Other causative Candida species are Candida tropicalis, Candida glabrata, Candida parapsilosis and Candida dubliniensis. C. dubliniensis is biologically closer than other species to, and often misdiagnosed with, C. albicans[28,29]. During delivery or soon after birth, the gastrointestinal tract is colonized by this fungus, which then becomes a normal human commensal. It is frequently isolated from the skin, oral and vaginal cavity of healthy individuals. Candida albicans is a eukaryotic diploid microorganisms with a complex lifecycle, which includes a sexual phase (mating), and different forms of growth, mostly represented in vivo by unicellular yeast and multicellular hyphal cells. The latter largely predominate in mucosal infections. Hyphal cells are formed through the so-called dimorphic transition, a very important biological phenomenon, one of many consequences for the host–Candida relationship.

Back to Top | Article Outline

Dimorphic transition

Hyphae of C. albicans are generated by yeast form cells through the formation of short germ tubes (Figs 1 and 2) which by further elongation and branching brings about a true mycelium. Nets of intertwining mycelia form a biofilm on the epithelia, which together with recruited neutrophils, macrophages, tissue matrix and cellular debris are major constituents of the typical fungal plaque (the ‘thrush’). Germ tubes are easily induced and monitored in vitro and have therefore been intensely studied for a comprehension of the mechanisms underlying hyphal formation. Serum, but also simple compounds such as saccharides and amino acids, with or without CO2, and a temperature of 37°C can induce germ tube formation. This process occurs by activation of diverse, multiple signaling cascades such as the Efg1-mediated cyclic adenosine monophosphate (cAMP) and the Cph1-mediated mitogen-activated protein kinase (MAPK) pathways, with Ras1 likely functioning as master upstream regulator of both pathways (reviewed in [30]). Hyphal development can be inhibited by farnesol, an autoregulatory compound, which inhibits Ras1–cAMP pathway [31].

Induction of hyphal transformation in vivo is less understood. However, it is likely that biochemical inducers liberated from serum or tissues, in particular from the gastrointestinal tract where bacteria can degrade food nutrients and produce amino acids, bacterial cell wall degradation products such as muramyl dipeptide and acetylglucosamine, are playing a role [32–34].

Back to Top | Article Outline

White–opaque switch

Yeast cells, which generate typical white colonies on solid media, can also undergo a spontaneous, low-frequency transition to slightly elongated cells which produce characteristic opaque colonies (Fig. 2). This ‘white–opaque switch’ is a unique phenomenon, essential for fungal mating and completion of a ‘parasexual’ cycle. In this cycle, the tetraploid cells resulting from mating of two sex-competent diploid cells return to diploidy not by meiosis but by loss of chromosomes. Mating is induced by pheromones. One identified pheromone is a 13-amino acid peptide. White–opaque switch has important consequences on C. albicans pathogenicity, particularly on the mucosa, by affecting fungal adherence and biofilm formation (quorum sensing). N-Acetyl-D-glucosamine, a main inducer of hyphal transition in C. albicans is also an inducer of white–opaque switch [32–35]. Actually, hyphal transition, white–opaque switch and biofilm formation are closely linked phenomena incorporating much of C. albicans distinctive biology and pathogenicity.

Back to Top | Article Outline

The cell wall of Candida albicans

All forms of Candida growth have a complex cell wall which actually determines fungal morphology and ensures viability under osmotic and other stresses. Yeast and hyphal cells express on their surface different combinations of polysaccharides (such as mannan, β-glucan and chitin) and saccharide–protein complexes recognized by host receptors (pattern recognition receptors; PRRs) as pathogen-associated molecular pattern (PAMP) [36,37] (Figs 1 and 3).

Back to Top | Article Outline

Consequences of morphology changes of Candida albicans

Although the biological reasons for the accentuated polymorphism of C. albicans are poorly known, its consequence on host–Candida relationship is rather certain. Particularly, hyphal growth has a tremendous impact on the host. The yeast form cells (at least up to a certain number of them) are well tolerated since they are kept at bay by various potent responses from innate and adaptive immunity [36,38–40]. In contrast, the hyphal cells express an increased capacity to adhere to epithelial cells, often in the form of drug-recalcitrant biofilm [41], resist phagocytosis and invade the epithelial tissue. Entrance into the epithelial barrier can occur by endocytosis or by active penetration and cause epithelial cell damage mechanically and/or through the elaboration of virulence factors [40] (Fig. 4). A number of putative virulence factors have been described in C. albicans (Table 3). One of the best characterized among these factors is the secreted aspartyl proteinase (Sap) protein family [42–44].

Back to Top | Article Outline

The secreted aspartyl proteinases

The secreted aspartyl proteinases (Saps) of C. albicans constitute a family of at least 10 related members (Sap1–Sap10) with different, although partially redundant, functions in fungal biology and virulence (Fig. 5 and Table 3). Each Sap can be expressed during infection though with different kinetics, magnitude and impact on pathogenesis, depending on the kind of infection, particularly mucosal or systemic [42,45–47]. Sap members have generally low substrate specificity and, at least in vitro, are capable of degrading most host proteins at the epithelial sites, inclusive of matrix and cell surface proteins such as keratin, fibronectin and E-cadherin, the main component of cell junctions [42,48–50]. In addition, they can hydrolyze antibodies and complement [51]. For these and possibly other activities (biofilm formation), Saps are critically involved in adherence and damage of epithelial barrier (Figs 4 and 5). Recent data also suggest a direct inflammation-inducing activity by some Sap through the activation of NLRP3 inflammasome [52].

Back to Top | Article Outline

The immune response

Humans appear to be well equipped for an effective control of excess C. albicans growth on epithelia by holding in check its aggressive traits. In particular, the epithelial tissue sharply discriminates the two forms of C. albicans growth and strongly reacts to attempts of invasion by the hyphae by several immune mechanisms, as described below.

The epithelial defensive asset and its capacity of sensing the differences between yeast and hyphae of C. albicans.

The epithelium constitutes a physical, microbiological and immunological barrier opposing to microbial attack. The physical barrier is per se insufficient to keep microbial pathogens at bay, including the opportunistic ones such as C. albicans. Fungal adherence, epithelium penetration and damage are hindered by the competing bacterial commensals and the presence of IgG and IgA antibodies, antimicrobial compounds, particularly lactoferrin and peptides generated by the epithelial cells themselves and other cells of the innate immune system patrolling the mucosa. Calcineurin, histatin-5 and β-defensins are notable examples of such compounds [39,53–56].

This defensive armamentarium can be further expanded by recruitment of anticandidal effector cells and production of pro-inflammatory cytokines. This process occurs when the epithelial cells, through the interaction of their receptors (which include almost all Toll-like, C-lectin like and NOD-like receptors found in the myeloid cells) with fungal PAMP sense the danger represented by the overwhelming growth of hyphal cells of C. albicans. In fact, the capacity of discriminating the commensal yeast form from the aggressive hyphal cells of the fungus is an essential attribute of the epithelium.

Some relevant aspects of this discriminatory ability have recently been reported [57,58]. Epithelial tissue can respond to the presence of the fungus by a two-phase MAPK pathway. In the first phase, a moderate MAPK activation which does not bring about an inflammatory cytokine response occurs, and this is a response that tolerates the presence of a limited number of yeast cells, as in the commensal state. A second MAPK activation phase is much more robust, as it involves an additional MAPK pathway that leads to the activation of MAPK phosphatase and pro-inflammatory cytokine production such as IL-1 and IL-6 [57,58]. In addition, hyphae stimulates activation of inflammasomes such as NLRP3 and NLRC4 (the latter appears prominent in the oral mucosa [59]) and leads to production of IL-1β and IL-18 through the caspase 1 pathway. Ultimately, both patterns of activation, particularly the NLRC4 inflammasome, regulate Th17 cells [59] and the consequent downstream production/recruitment of those humoral and cellular factors which, if effectively regulated, can efficiently oppose candidal invasion, inflammation and destruction of the epithelium.

Back to Top | Article Outline

The role of CD4+ T helper cells

Commensalism also stimulates robust, lifelong humoral and cellular adaptive immune responses, including activities involving both CD4+ and CD8+ T cells. These cells cooperate with innate immunity to control fungal growth but are unable to (and probably need not) eradicate it. In line with the demonstrated association of HIV-induced CD4 T-cell loss in the manifestation of OPC and OEC, Th1 and Th17 cell responses in animal models appear to be instrumental for mucosal protection [36,60]. However, the magnitude of the relative contributions to these immune activities, their immunomodulation by regulatory T cells (Treg) and the fine mechanisms of immune protection have long remained elusive.

More recent data highlight an early, primary defensive role for Th17 cell functional subset with the Th17 cytokine signature IL-17 (A and F) and IL-22, possibly strengthened/regulated by Th1/Treg cells [60–63]. Th17 cytokines link CD4 cells to a PMN response with a group of soluble antimicrobial peptides and chemokines collaborating to fight the fungus on the epithelia (Figs 6 and 7). Recent data also suggest that other participants of mucosal lymphoid tissues, such as the Candida-specific Vdelta1 T lymphocytes which co-express both Th1 and Th17 biomarkers and produce the two respective cytokine signatures interferon-γ and IL-17, may play a role [64]. Notably, these cells are expanded in the HIV-positive patients possibly as an attempt to fill the defensive gap generated by CD4 cell loss.

Back to Top | Article Outline

CD8 T cells and antibodies

It is debated whether CD8 T cells and their cytokines can mediate, or even exert, anticandida activity in the absence of CD4 cells. CD8 T cells (particularly the activated memory CD8 T cells) are highly represented in the human mucosa and can be attracted to the epithelium by IL8 produced by keratinocytes. E-cadherin binding also helps CD8 cells traffic from mucosa to the epithelium [20,39,40]. In addition, CD8 cells can exert cytotoxic activity against keratinocytes expressing Candida antigens after fungal internalization or can enhance activity of other effector cells like macrophages and neutrophils. Finally, there are conflicting reports about any direct capacity of IL-2-activated T and natural killer cells to bind and kill directly the fungus [65,66]. In any case, these CD8 cell-mediated mechanisms are evidently unable to control fungal growth in the absence of a CD4 cell counterpart [6,8]. Rather, the CD8 cells (particularly those expressing the CD38 marker) are an important signal of immune activation and disease progression in HIV-positive patients.

A substantial antibody response, mostly directed against immunodominant components of the fungal cell wall such as the mannoproteins, is also elicited by C. albicans colonization. Their levels and specificity do not seem to change during HIV infection and the associated B-cell activation and hypergammaglobulinemia [67]. Although most dominant antibodies appear to be ineffective for protection against oral disease, or could even enhance the disorder by deviating a protective host response, some protective specificities and isotypes have been reported. These factors may be of relevance in vaccine-induced immunoprotection [68,69] (see below).

Back to Top | Article Outline

Disease determination

Loss of CD4 T helper cells with a switch from a protective Th1 to a nonprotective Th2 cytokine profile has long been advocated to be the immunological determinant of HIV infection progressing to AIDS, with the emergence of opportunistic infections including candidiasis [70]. The Th17 cell functional subset within the CD4 T-cell lineage now appears to be selectively depleted with the progression of HIV infection. In contrast, Th17 cells are well preserved, as the overall circulating CD4 T cells, in the HIV-infected long-term nonprogressors, and are restored in association with ART [71–73]. Together with evidence from experimental infections and gene polymorphism studies [27,63,74], a close link has become plausible between depletion of Th17 subset and the onset/progression of mucosal candidiasis. In this mechanistic scenario, the selective depletion of Th17 cells during the progression of HIV infection is the critical host determinant of C. albicans overwhelming the epithelial defense and cause disease.

In addition, Th17 cell loss can facilitate translocation of microbial components from the intestine giving rise to the other distinctive hallmark of HIV infection that is the progressive immune activation that can also bring exhaustion of lymphopoiesis [4,74]. In addition to lipopolysaccharide (LPS), we detected Candida cell wall components in serum of AIDS patients (unpublished results). Mannoproteins and β-glucan components of this fungus have also been reported to be good inducers of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α not only from antigen-presenting cell and monocytes but also from PMN of HIV-positive patients [75–78]. Of interest, mannoprotein-stimulated neutrophils from HIV-positive patients, even at early stages of HIV infection, similar to LPS-stimulated neutrophils, produced more IL-6 and TNF-α than equally stimulated neutrophils from healthy uninfected controls [76].

Other inflammation-inducing fungus components may be the Sap [52,79], the secretion of which is particularly abundant in the HIV-positive patients (see below). Overall, the general picture is consistent with the notion that OPC and OEC are manifested when the CD4 cells, and in particular the Th17 CD4 functional subset, are deeply depleted. Other contributory events can be the HIV-induced alterations in cells patrolling mucosal epithelia, and the limited yet viable capacity of HIV to infect epithelial cells expressing CXCR4 and ceramide receptors [80–82]. The data also suggest that Candida components add to other microbial constituents, in particular the LPS, in causing the immune activation of HIV-positive patients. Promotion of excessive inflammatory response could also affect the evolution of candidiasis itself [62–64].

Back to Top | Article Outline

What of HIV, what of Candida and what of both

The evidence that loss/dysregulation of immune responses plays a critical role in the determination of OPC and still more of OEC is rather substantial. Nonetheless, the rich armamentarium of anticandidal immunity, centered on close collaboration and integration between tissue barriers, innate and adaptive immune responses, would suggest that growth of a ‘commensal’, with ‘low-pathogenicity’ microbe such as C. albicans could still be controlled on the epithelia. This event does not happen because this fungus is not a benign passive participant in the disease onset and outcome. First of all, C. albicans, particularly when grown under hyphal forms, has the potential to express a number of immunoevasion factors. As shown in Table 4, these factors can modify or divert critical anticandidal responses of both innate and adaptive immunity, including altered production of cytokines, disturbance of PMN phagocytosis and killing and degradation of defensive proteins [51,75,76,83–86]. Although it is likely that none of the above factors alone is so pervasive as to account by itself for fungus escaping from host response, their cooperation can support an aggressive characteristic, particularly in a host with impaired defense such as the HIV-positive patient.

More in general, C. albicans finds in the HIV-positive patient a favorable environment for overexpression of its ‘virulence’ attributes which can eventually contribute to the immune dysregulated state of HIV-positive patient. Most notable is the accelerated hyphal growth and the marked enhancement of Sap production. This latter phenomenon has been repeatedly reported to occur both in the oral and the vaginal cavity of HIV-positive patients [87–91]. Enhanced Sap production is detected in vivo and increases with advancing stages of HIV infection. Intriguingly, this phenomenon could derive from the capacity of the virus to stably bind to the fungus and/or by Sap induction by the HIV envelope (GP160) or other viral proteins such as Tat [92,93]. Whether overexpression of virulence traits or even selection of more virulent fungal genotypes is due to the HIV binding itself or induction by HIV proteins or by other events, has not been established. Whatever the mechanisms, and owing to the Sap properties mentioned above [48–52], Sap gene overexpression and/or selection of high Sap producer genotypes may represent a primary pathogenicity hit for mucosal infection and contribute to immune activation.

Back to Top | Article Outline

The case for HIV and Candida albicans proteinases

HIV proteinase is also an aspartyl proteinase, sharing an elevated sequence homology with C. albicans Sap, particularly Sap2. The viral proteinase perhaps is an antecedent of eukaryotic Saps (Fig. 4). Consequently, and more importantly, inhibitors of HIV proteinase present in the ART cocktail inhibit Candida Sap in vitro and in vivo[94–98]. This finding, in conjunction with some clinical impressions [94,95], has led ourselves and others to postulate that the early, dramatic reduction of OPC in patients under ART is also due to a direct anticandidal activity of HIV proteinase inhibitors present in ART, adding, and perhaps also favoring, the known immune reconstitution of CD4 cells [94–98]. These observations have been expanded to other fungi [99,100] and malaria parasites [101] and have generated interest in novel class of anticandidal drugs having Sap as a target [102].

A second intriguing commonality is that the saccharide epitope recognized by the 2G12 antibody, a broadly neutralizing anti-HIV antibody, is also shared by C. albicans (and C. tropicalis) [103,104]. Finally, peptides from HIV regulatory proteins such Rev and Tat have been reported to possess antifungal activity, with different mechanisms [105,106]. These are probably related to mechanisms shared by many other antibody-derived antimicrobial peptides [107], one of which affects HIV by co-receptor mimicry [108] (Table 5).

Back to Top | Article Outline

Therapy and vaccines

Therapy of mucosal candidiasis is effective but, as has happened for the general antibiotic therapy, is under increasing threat by the emergence of resistance to antimycotics particularly the well tolerated triazole drugs (Table 6). Refractory or resistant OPC is not unusual particularly following maintenance administration of fluconazole [16,17,109–112]. Complex chromosomal rearrangements and expression of drug efflux pumps have been described in azole-resistant C. albicans and C. glabrata, also associated with enhanced virulence [113,114]. Current attempts to improve therapeutic approaches in azole-resistant strains include the use of both old (nystatin, amphothericin B) and new (echinocandin derivatives such as caspofungin and micafungin) drugs [115–120]. These latter compounds are candidacidal because they inhibit a critical step of cell wall synthesis (glucan synthase) somewhat reminiscent of the lytic action of penicillin against bacteria. However, resistance to glucan-synthase inhibitors has also emerged in the HIV setting [121]. In the absence of host cooperation, particularly with the large set of immune dysfunctions typical of HIV-infected patients, antifungal therapy remains ineffective in the long run. This fact has prompted the search for new approaches in anti-Candida drugs including Sap peptidomimetics inhibitors [122]. Some of these have shown appreciable activity in vitro and in a model of vaginal candidiasis in rats challenged by a fluconazole-resistant strain of C. albicans[123].

The threat of antifungal resistance and the widespread occurrence of other severe Candida pathologies (e.g. vulvovaginal recurrent candidiasis, candidemia, deep-seated candidiasis) have also hastened the search for preventive measures among which vaccination would constitute the most beneficial. It would seem rather naive to propose a vaccination approach in patients who are already naturally immunized against Candida through the lifelong commensalism, particularly in the setting of incurrent and heavy immunodepression. Nonetheless, progress in understanding the multifaceted nature of host immunity to Candida even in the immunocompromised patient suggests that vaccination against the fungus is feasible (reviewed in [68,69]). Notably, the loss of preexisting anti-Candida immunity in the setting of HIV infection can even facilitate vaccination, as preexisting immunity could bias or distort induction of immune responses to vaccine neo-antigens. In this context, particular advantageous are those approaches which are based on the elicitation of neutralizing antibodies against antigens which are not or are poorly expressed during the commensal life [124–129]. Other vaccines address antigens capable of strong and persistent stimulation of Th17 cells [129,130] (Table 6). Two vaccines are actually undergoing phase 1 clinical trials in Europe and USA. They use whole protein or fragments derived from Sap2 or Als3 adhesin as immunogens and human-compatible alum or oil-in-water emulsions or virosomal particles as adjuvants [129,131]. Although these vaccines are directed at fighting candidiasis in nonimmunocompromised patients, their initial validation could be a premise for possible extension to HIV-positive patients.

Back to Top | Article Outline


Candida albicans interaction with humans is an example of a very successful adaptation, at the extreme of a semi-symbiotic relationship, with the healthy host. Conversely, this interaction may cross the border separating safe commensalism from opportunistic behavior and frank pathogenicity in an immune-dysregulated or debilitated host. Candida albicans is as successful as a human commensal, as it is as human pathogen. Its relationship with the HIV-positive patient is truly paradigmatic of how an opportunistic microbe can both efficiently exploit the virus-induced damage of the immune system as well as mobilize its armory for the breakage of the epithelial barrier. In trespassing the epithelial barrier, the fungus likely exploits its ability to deceive or escape from host immunity. This ability is due to a number of ‘virulence’ factors largely incorporated and expressed in morphology changes such as the yeast-to-hypha transition, and white–opaque switch.

From this point of view, studies on C. albicans and candidiasis constitute a unique model for obtaining important insight into the relationship between the microbial habit of growth and the host response. Investigations on mucosal candidiasis and HIV–Candida co-pathogenesis have greatly contributed to the notion that a functional subset of T helper cells, the Th17, possibly in association with the Th1 subset and under regulation by Treg cells, plays a critical role in the defense against mucosal candidiasis. These studies are also encouraging the efforts of changing or integrating current anticandidal chemotherapy with novel approaches targeting the main virulence factors (e.g. Sap) and vaccine approaches.

Studies on the co-pathogenic interaction between C. albicans and HIV are highlighting many intriguing biological aspects which derive from HIV interaction with the fungus. They include the capacity of the virus to bind to the fungus and the virus-induced enhancement of its virulence potential. Finally, the capacity of C. albicans itself and some of its main pathogenic constituents to participate in the process of chronic inflammation and immune activation so evident in the HIV-positive patient [132], may add fuel to HIV pathogenesis.

Many aspects of host–Candida relationship ‘in vivo’ remain unclear. These include the issues of how pervasive are the fungal immune-escape mechanisms in vivo, the respective contributions of Th1 and Th17 cells, and possibly antibodies in the defense, whether and how other T cells such Treg and CD8 cells modulate and/or cooperate with their cytokines to the protection also avoiding excessive local inflammation, what kind of fungal components or product is actually recognized by either yeast or hyphae recognition receptors in the different forms and phases of C. albicans growth and the capacity of activating inflammasomes. Some recent suggestions implicate C. albicans Sap in addition to cell surface PAMP both in the phase of epithelium penetration and damage, and in inflammation. In addition to the human polymorphism studies, most of the relevant information comes from experimental murine models and in-vitro studies with human reconstituted epithelium. However, direct translation of these data to human disease must be taken cautiously. All this requires further investigations aimed at unraveling the multifaceted aspects of Candida behavior in the HIV setting. These studies will certainly contribute to a more effective control of the organism and also provide useful information on the HIV–host relationship itself that can assist the fight against the virus.

Note: When this manuscript was at the proof stage, a paper by Zelante et al.[133] was published showing that C. albicans can bind IL-17A and exploits this binding to enhance its virulence potential. This would be an important addition to the above-described mechanisms this fungus can employ to evade an immune response critical for host defense.

Back to Top | Article Outline


This review is dedicated to the memory of Giovanni B. Rossi, the invaluable director of AIDS research in Italy through the promotion of the National AIDS Research Program. Almost all of the personal research quoted by the authors in this review has been promoted by that research program over many years.

Special thanks are also due to Marisa Colone and Annarita Stringaro, Derek Sullivan, Antonella Torosantucci and Flavia De Bernardis for kindly providing Figs 1, 3, 4 and 5 respectively. Finally, we are particularly grateful to the AIDS Editor Jay Levy for invitation to write this review, for his valuable suggestions and editing, and continuous support. A.M., R.G., A.D.M. and M.F. helped in the preparation of the manuscript.

A.C. is supported by AIDS research Contract F/112, R.C. by AIDS Research Contract 40H35 and Fondazione Roma, ‘Peptidomimetic inhibitors of aspartyl proyeinases as innovative therapeutics for HIV and Candida albicans infections’.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


1. Klein RS, Harris CA, Small CB, Moll B, Lesser M, Friedland GH. Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. N Engl J Med 1984; 311:354–358.
2. Tavitian A, Raufman JP, Rosenthal LE. Oral candidiasis as a marker for esophageal candidiasis in the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104:54–55.
3. Guihot A, Bourgarit A, Carcelain G, Autran B. Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. Trends Immunol 2011; 32:131–137.
4. Sauce D, Larsen M, Fastenackels S, Pauchard M, Ait-Mohand H, Schneider L, et al. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood 2011; 117:5142–5151.
5. Pakker NG, Roos MT, van Leeuwen R, de Jong MD, Koot M, Reiss P, et al. Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:318–326.
6. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.
7. Powderly WG, Landay A, Lederman MM. Recovery of the immune system with antiretroviral therapy. The end of opportunism?. JAMA 1998; 280:72–77.
8. Sangeorzan JA, Bradley SF, He X, Zarins LT, Ridenour GL, Tiballi RN, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med 1994; 97:339–346.
9. Huppmann AR, Orenstein JM. Opportunistic disorders of the gastrointestinal tract in the age of highly active antiretroviral therapy. Hum Pathol 2010; 41:1777–1787.
10. Vazquez JA. Invasive oesophageal candidiasis. Drugs 2003; 63:921–932.
11. Thompson GR 3rd, Patel PK, Kirkpatrick WR, Westbrook SD, Berg D, Erlandsen J, et al. Oropharyngeal candidiasis in the era of antiretroviral therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109:488–495.
12. Traeder C, Kowoll S, Arastéh K. Candida infection in HIV positive patients 1985–2007. Mycoses 2008; 51 (Suppl 2):58–61.
13. Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 1998; 26:556–565.
14. Nkuize M, De Wit S, Muls V, Arvanitakis M, Buset M. Upper gastrointestinal endoscopic findings in the era of highly active antiretroviral therapy. HIV Med 2010; 11:412–417.
15. Ohmit SE, Sobel JD, Schuman P, Duerr A, Mayer K, Rompalo A, et al. HIV Epidemiology Research Study (HERS) GroupLongitudinal study of mucosal Candida species colonization and candidiasis among human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis 2003; 188:118–127.
16. Revankar SG, Kirkpatrick WR, McAtee RK, Dib OP, Fothergill AW, Redding SW, et al. Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients. J Infect Dis 1996; 174:821–827.
17. Revankar SG, Sanche SE, Dib OP, Caceres M, Patterson TF. Effect of highly active antiretroviral therapy on recurrent oropharyngeal candidiasis in HIV-infected patients. AIDS 1998; 12:2511–2513.
18. Revankar SG, Dib OP, Kirkpatrick WR, McAtee RK, Fothergill AW, Rinaldi MG, et al. Clinical evaluation and microbiology of oropharyngeal infection due to fluconazole-resistant Candida in human immunodeficiency virus-infected patients. Clin Infect Dis 1998; 26:960–963.
19. Revankar SG, Kirkpatrick WR, McAtee RK, Dib OP, Fothergill AW, Redding SW, et al. A randomized trial of continuous or intermittent therapy with fluconazole for oropharyngeal candidiasis in HIV-infected patients: clinical outcomes and development of fluconazole resistance. Am J Med 1998; 105:7–11.
20. Fidel PL. Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis. Adv Dent Res 2011; 23:45–49.
21. Challacombe SJ, Naglik JR. The effects of HIV infection on oral mucosal immunity. Adv Dent Res 2006; 19:29–35.
22. Fidel PL Jr. Distinct protective host defenses against oral and vaginal candidiasis. Med Mycol 2002; 40:359–375.
23. Pappas PG. Invasive candidiasis. Infect Dis Clin North Am 2006; 20:485–506.
24. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:503–535.
25. Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998; 178:203–211.
26. Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Clin Infect Dis 2012; 54:424–433.
27. Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332:65–68.
28. Gutiérrez J, Morales P, González MA, Quindós G. Candida dubliniensis, a new fungal pathogen. J Basic Microbiol 2002; 42:207–227.
29. Moran GP, Coleman DC, Sullivan DJ. Candida albicans versus Candida dubliniensis: why is C. albicans more pathogenic?Int J Microbiol 2012. doi: 10.1155.2012.205921.
30. Biswas S, Van Dijck P, Datta A. Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans. Microbiol Mol Biol Rev 2007; 71:348–376.
31. Hall RA, Turner KJ, Chaloupka J, Cottier F, De Sordi L, Sanglard D, et al. The quorum sensing molecule farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans eukaryot. Cell 2011; 10:1034–1042.
32. Soll DR. Why does Candida albicans switch?. FEMS Yeast Res 2009; 9:973–989.
33. Bennett RJ, Uhl MA, Miller MG, Johnson AD. Identification and characterization of a Candida albicans mating pheromone. Mol Cell Biol 2003; 23:8189–8201.
34. Simonetti n, Strippoli V, Cassone A. Yeast-mycelial transition induced by N-acetyl-D-glucosamine in Candida albicans. Nature 1974; 250:344–346.
35. Huang G, Yi S, Sahni N, Daniels KJ, Srikantha T, Soll DR. N-Acetylglucosamine induces white to opaque switching: a mating prerequisite in Candida albicans. PLoS Pathog 2010; 6:3. doi: 10.1371.
36. Romani L. Immunity to fungal infections.Nat Rev Immunol 201; 11:275–288.
37. Cheng SC, Joosten LA, Kullberg BJ, Netea MG. The interplay between Candida albicans and the mammalian innate host defense.Infect Immun 2012 80 :1304–1313.
38. Zhu W, Filler SG. Interactions of Candida albicans with epithelial cells. Cell Microbiol 2010; 12:273–282.
39. Weindl G, Wagener J, Schaller M. Epithelial cells and innate antifungal defense. J Dent Res 2010; 89:666–675.
40. Naglik JR, Moyes DL, Wächtler B, Hube B. Candida albicans interactions with epithelial cells and mucosal immunity. Microbes Infect 2011; 13:963–976.
41. Ganguly S, Mitchell AP. Mucosal biofilms of Candida albicans. Curr Opin Microbiol 2011; 14:380–385.
42. Naglik JR, Challacombe SJ, Hube B. Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol Mol Biol Rev 2003; 67:400–428.
43. De Bernardis F, Sullivan PA, Cassone A. Aspartyl proteinases of Candida albicans and their role in pathogenicity. Med Mycol 2001; 39:303–313.
44. Monod M, Borg-von ZM. Secreted aspartic proteases as virulence factors of Candida species. Biol Chem 2002; 383:1087–1093.
45. Correia A, Lermann U, Teixeira L, Cerca F, Botelho S, da Costa RM, et al. Limited role of secreted aspartyl proteinases Sap1 to Sap6 in Candida albicans virulence and host immune response in murine hematogenously disseminated candidiasis. Infect Immun 2010; 78:4839–4849.
46. Naglik JR, Moyes D, Makwana J, Kanzaria P, Tsichlaki E, Weindl G, et al. Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis. Microbiology 2008; 154:3266–3280.
47. Naglik JR, Rodgers CA, Shirlaw PJ, Dobbie JL, Fernandes-Naglik LL, Greenspan D, et al. Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B genes in humans correlates with active oral and vaginal infections. J Infect Dis 2003; 188:469–479.
48. Frank CF, Hostetter MK. Cleavage of E-cadherin: a mechanism for disruption of the intestinal epithelial barrier by Candida albicans. Transl Res 2007; 149:211–222.
49. Quimby K, Lilly E, Zacharek M, McNulty K, Leigh J, Vazquez J, et al. CD8 T cells and E-cadherin in host responses against oropharyngeal candidiasis. Oral Dis 2012; 18:153–161.
50. Villar CC, Kashleva H, Nobile CJ, Mitchell AP, Dongari-Bagtzoglou A. Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p. Infect Immun 2007; 75:2126–2135.
51. Gropp K, Schild L, Schindler S, Hube B, Zipfel PF, Skerka C. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol Immunol 2009; 47:465–475.
52. Pietrella D, Rachini A, Pandey N, Schild L, Netea M, Bistoni F, et al. The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infect Immun 2010; 78:4754–4762.
53. Chen YL, Brand A, Morrison EL, Silao FG, Bigol UG, Malbas FF Jr. Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. Eukaryot Cell 2011; 10:803–819.
54. Meiller TF, Hube B, Schild L, Shirtliff ME, Scheper MA, Winkler R, et al. A novel immune evasion strategy of Candida albicans: proteolytic cleavage of a salivary antimicrobial peptide. PLoS One 2009; 4:e5039.
55. Brandtzaeg P, Gabrielsen TO, Dale I, Müller F, Steinbakk M, Fagerhol MK. The leucocyte protein L1 (calprotectin): a putative nonspecific defence factor at epithelial surfaces. Adv Exp Med Biol 1995; 371:201–206.
56. Mathews M, Jia HP, Guthmiller JM, Losh G, Graham S, Johnson GK, et al. Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immun 1999; 67:2740–2745.
57. Moyes DL, Runglall M, Murciano C, Shen C, Nayar D, Thavaraj S, et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 2010; 8:225–235.
58. Gow NA, van de Veerdonk FL, Brown AJ, Netea MG. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 2011; 10:112–122.
59. Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, et al. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog 2011; 7:e1002379.
60. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 2009; 206:299–311.
61. Favre D, Mold J, Hunt PW, Kanwar B, Loke P, Seu L, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2010; 2:32–36.
62. De Luca A, Zelante T, D’Angelo C, Zagarella S, Fallarino F, Spreca A, et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol 2010; 3:361–373.
63. Pietrella D, Rachini A, Pines M, Pandey N, Mosci P, Bistoni F, et al. Th17 cells and IL-17 in protective immunity to vaginal candidiasis. PLoS One 2011; 6:e22770.
64. Fenoglio D, Poggi A, Catellani S, Battaglia F, Ferrera A, Seti M, et al. Vdelta1 T lymphocytes producing IFNg patients and IL-17 are expanded in HIV-infected and respond to Candida albicans. Blood 2009; 113:6611–6618.
65. Beno DW, Stöver AG, Mathews HL. Growth inhibition of Candida albicans hyphae by CD8+ lymphocytes. J Immunol 1995; 154:5273–5281.
66. Arancia G, Molinari A, Crateri P, Stringaro A, Ramoni C, Dupuis ML, et al. Noninhibitory binding of human interleukin-2-activated natural killer cells to the germ tube forms of Candida albicans. Infect Immun 1995; 63:280–288.
67. Haas A, Zimmermann K, Graw F, Slack E, Rusert P, Ledergerber B, et al. Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection. Gut 2011; 60:1506–1519.
68. Cutler JE, Deepe GS, Klein D. Advances in combating fungal diseases: vaccines on the threshold. Nat Rev Microbiol 2007; 5:13–28.
69. Cassone A. Fungal vaccines: real progress from real challenge. Lancet Infect Dis 2008; 8:114–124.
70. Clerici M, Shearer GM. A TH1→TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993; 14:107–111.
71. Demberg T, Ettinger AC, Aladi S, McKinnon K, Kuddo T, Venzon D, et al. Strong viremia control in vaccinated macaques does not prevent gradual Th17 cell loss from central memory. Vaccine 2011; 29:6017–6028.
72. Ciccone EJ, Greenwald JH, Lee PI, Biancotto A, Read SW, Yao MA, et al. CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. J Virol 2011; 85:5880–5888.
73. Salgado M, Rallón NI, Rodés B, López M, Soriano V, Benito JM. Long-term nonprogressors display a greater number of Th17 cells than HIV-infected typical progressors. Clin Immunol 2011; 139:110–114.
74. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441:235–238.
75. Torosantucci A, Chiani P, Cassone A. Differential chemokine response of human monocytes to yeast and hyphal forms of Candida albicans and its relation to the beta-1,6 glucan of the fungal cell wall. J Leukoc Biol 2000; 68:923–932.
76. Torosantucci A, Chiani P, Ausiello CM, Mezzaroma I, Cassone A. Responsiveness of human polymorphonuclear cells (PMNL) to stimulation by a mannoprotein fraction (MP-F2) of Candida albicans :enhanced production of IL-6 and tumor necrosis factor-alpha(TNF-alpha) by MP-F2-stimulated PMNL from HIV-infected subjects. Clin Exp Immunol 1997; 107:451–457.
77. Cassone A, Chiani P, Quinti I, Torosantucci A. Possible participation of polymorphonuclear cells stimulated by microbial immunomodulators in the dysregulated cytokine patterns of AIDS patients. J Leukoc Biol 1997; 62:60–66.
78. Nisini R, Torosantucci A, Romagnoli G, Chiani P, Donati S, Gagliardi MC, et al. beta-Glucan of Candida albicans cell wall causes the subversion of human monocyte differentiation into dendritic cells. J Leukoc Biol 2007; 82:1136–1142.
79. Schaller M, Mailhammer R, Grassl G, Sander CA, Hube B, Korting HC. Infection of human oral epithelia with Candida species induces cytokine expression correlated to the degree of virulence. J Invest Dermatol 2002; 118:652–657.
80. Kazmi SH, Naglik JR, Sweet SP, Evans RW, O'Shea S, Banatvala JE, et al. Comparison of human immunodeficiency virus type 1-specific inhibitory activities in saliva and other human mucosal fluids. Clin Vaccine Immunol 2006; 13:1111–1118.
81. Blauvelt A, Clerici M, Lucey DR, Steinberg SM, Yarchoan R, Walker R, et al. Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. J Immunol 1995; 154:3506–3515.
82. Qureshi MN, Barr CE, Hewlitt I, Boorstein R, Kong F, Bagasra O, et al. Detection of HIV in oral mucosal cells. Oral Dis 1997; 3 (Suppl 1):S73–S78.
83. Frohner IE, Bourgeois C, Yatsyk K, Majer O, Kuchler K. Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance. Mol Microbiol 2009; 71:240–252.
84. Luo S, Blom AM, Rupp S, Hipler UC, Hube B, Skerka C, et al. The pH-regulated antigen 1 of Candida albicans binds the human complement inhibitor C4b-binding protein and mediates fungal complement evasion. J Biol Chem 2011; 286:8021–8029.
85. Mora-Montes HM, Netea MG, Ferwerda G, Lenardon MD, Brown GD, Mistry AR, et al. Recognition and blocking of innate immunity cells by Candida albicans chitin. Infect Immun 2011; 79:1961–1970.
86. de Boer AD, de Groot PW, Weindl G, Schaller M, Riedel D, Diez-Orejas R. The Candida albicans cell wall protein Rhd3/Pga29 is abundant in the yeast form and contributes to virulence. Yeast 2010; 27:611–624.
87. De Bernardis F, Chiani P, Ciccozzi M, Pellegrini G, Ceddia T, D’Offizzi G, et al. Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus. Infect Immun 1996; 64:466–471.
88. Heilmann CJ, Sorgo AG, Siliakus AR, Dekker HL, Brul S, de Koster CG, et al. Hyphal induction in the human fungal pathogen Candida albicans reveals a characteristic wall protein profile. Microbiology 2011; 157:2297–2307.
89. Mane A, Gaikwad S, Bembalkar S, Risbud A. Increased expression of virulence attributes in oral Candida albicans isolates from human immunodeficiency virus-positive individuals. J Med Microbiol 2012; 61:285–290.
90. Ripeau JS, Fiorillo M, Aumont F, Belhumeur P, de Repentigny L. Evidence for differential expression of Candida albicans virulence genes during oral infection in intact and human immunodeficiency virus type 1-transgenic mice. J Infect Dis 2002; 185:1094–1102.
91. Vargas KG, Joly S. Carriage frequency, intensity of carriage, and strains of oral yeast species vary in the progression to oral candidiasis in human immunodeficiency virus-positive individuals. J Clin Microbiol 2002; 40:341–350.
92. Gruber A, Lell CP, Speth C, Stoiber H, Lass-Flörl C, Sonneborn A, et al. Human immunodeficiency virus type 1 Tat binds to Candida albicans, inducing hyphae but augmenting phagocytosis in vitro. Immunology 2001; 104:455–461.
93. Gruber A, Lukasser-Vogl E, Borg-von Zepelin M, Dierich MP, Würzner R. Human immunodeficiency virus type 1 gp160 and gp41 binding to Candida albicans selectively enhances candidal virulence in vitro. J Infect Dis 1998; 177:1057–1063.
94. Cassone A, De Bernardis F, Torosantucci A, Tacconelli E, Tumbarello M, Cauda R. In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors. J Infect Dis 1999; 180:448–453.
95. De Bernardis F, Tacconelli E, Mondello F, Cataldo A, Arancia S, Cauda R, et al. Antiretroviral therapy with protease inhibitors decreases virulence enzyme expression in vivo by Candida albicans without selection of avirulent fungus strains or decreasing their antimycotic susceptibility. FEMS Immunol Med Microbiol 2004; 41:27–34.
96. Cassone A, Tacconelli E, De Bernardis F, Tumbarello M, Torosantucci A, Chiani P, et al. Antiretroviral therapy with protease inhibitors has an early, immune reconstitution-independent beneficial effect on Candida virulence and oral candidiasis in human immunodeficiency virus-infected subjects. J Infect Dis 2002; 185:188–195.97.
97. Cauda R, Tacconelli E, Tumbarello M, Morace G, De Bernardis F, Torosantucci A, et al. Role of protease inhibitors in preventing recurrent oral candidosis in patients with HIV infection: a prospective case-control study. J Acquir Immune Defic Syndr 1999; 21:20–25.
98. Gruber A, Speth C, Lukasser-Vogl E, Zangerle R, Borg-von Zepelin M, Dierich MP, Würzner R. Human immunodeficiency virus type 1 protease inhibitor attenuates Candida albicans virulence properties in vitro. Immunopharmacology 1999; 41:227–234.
99. Monari C, Pericolini E, Bistoni G, Cenci E, Bistoni F, Vecchiarelli A. Influence of indinavir on virulence and growth of Cryptococcus neoformans. J Infect Dis 2005; 191:307–311.
100. Palmeira VF, Kneipp LF, Rozental S, Alviano CS, Santos AL. Beneficial effects of HIV peptidase inhibitors on Fonsecaea pedrosoi: promising compounds to arrest key fungal biological processes and virulence. PLoS One 2008; 3:e3382.
101. Skimer-Adams T, McCarthy JS, Gardiner DL, Hilton PM, Andrews KT. Antiretroviral as antimalarial agents. J Infect Dis 2004; 190:1998–2000.
102. Braga-Silva LA, Santos AL. Aspartic protease inhibitors as potential anti-Candida albicans drugs: impacts on fungal biology, virulence and pathogenesis. Curr Med Chem 2011; 18:2401–2419.
103. Luallen RJ, Fu H, Agrawal-Gamse C, Mboudjeka I, Huang W, Lee FH, et al. A yeast glycoprotein shows high-affinity binding to the broadly neutralizing human immunodeficiency virus antibody 2G12 and inhibits gp120 interactions with 2G12 and DC-SIGN. J Virol 2009; 83:4861–4870.
104. Jung HJ, Park Y, Hahm KS, Lee DG. Biological activity of Tat (47-58) peptide on human pathogenic fungi.Biochem Biophys Res Commun 2006; 345:222–228.
105. Agrawal-Gamse C, Luallen RJ, Liu B, Fu H, Lee FH, Geng Y, et al. Yeast-elicited cross-reactive antibodies to HIV Env glycans efficiently neutralize virions expressing exclusively high-mannose N-linked glycans. J Virol 2011; 85:470–480.
106. Lee J, Lee DH, Lee DG. Candidacidal effects of Rev (11-20) derived from HIV-1 Rev protein. Mol Cells 2009; 28:403–406.
107. Polonelli L, Pontón J, Elguezabal N, Moragues MD, Casoli C, Pilotti E, et al. Antibody complementarity-determining regions (CDRs) can display differential antimicrobial, antiviral and antitumor activities. PLoS One 2008; 3:e2371.
108. Casoli C, Pilotti E, Perno CF, Balestra E, Polverini E, Cassone A, et al. A killer mimotope with therapeutic activity against AIDS-related opportunistic micro-organisms inhibits ex-vivo HIV-1 replication. AIDS 2006; 20:975–980.
109. He X, Tiballi RN, Zarins LT, Bradley SF, Sangeorzan JA, Kauffman CA. Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1994; 38:2495–2497.
110. Goldman M, Cloud GA, Wade KD, Reboli AC, Fichtenbaum CJ, Hafner R, et al. AIDS Clinical Trials Group Study Team 323; Mycoses Study Group Study Team 40. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40. Clin Infect Dis 2005; 41:1473–1480.
111. Grabar S, Lanoy E, Allavena C, Mary-Krause M, Bentata M, Fischer P, et al. Treatment of oral candidiasis in HIV infection. Oral Surg Oral Med Oral Pathol 1994; 78:211–215.
112. Hegener P, Troke PF, Fätkenheuer G, Diehl V, Ruhnke M. Treatment of fluconazole-resistant candidiasis with voriconazole in patients with AIDS. AIDS 1998; 12:2227–2238.
113. Schubert S, Barker KS, Znaidi S, Schneider S, Dierolf F, Dunkel N, et al. Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans. Antimicrob Agents Chemother 2011; 55:2212–2223.
114. Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS One 2011; 6:e17589.
115. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009; 58:1–207.
116. de Wet N, Llanos-Cuentas A, Suleiman J, Baraldi E, Krantz EF, Della Negra M, et al. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis 2004; 39:842–849.
117. Krause DS, Simjee AE, van Rensburg C, Viljoen J, Walsh TJ, Goldstein BP, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis 2004; 39:770–775.
118. Skiest DJ, Vazquez JA, Anstead GM, Graybill JR, Reynes J, Ward D, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis 2007; 44:607–614.
119. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001; 33:1529–1535.
120. Ostrowski-Zeichner L, Casadevall A, Galgiani JN, Odds FC, Rex JH. An insight into the antifungal pipeline: selected new molecules and beyond. Nat Rev Drug Discov 2010; 9:719–727.
121. Laverdière M, Lalonde RG, Baril JG, Sheppard DC, Park S, Perlin DS. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J Antimicrob Chemother 2006; 57:705–708.
122. Bein M, Schaller M, Korting HC. The secreted aspartic proteinases as a new target in the therapy of candidiasis. Curr Drug Targets 2002; 3:351–357.
123. Trabocchi A, Mannino C, Machetti F, De Bernardis F, Arancia S, Cauda R, et al. Identification of inhibitors of drug-resistant Candida albicans strains from a library of bicyclic peptidomimetic compounds. J Med Chem 2010; 53:2502–2509.
124. Chiani P, Bromuro C, Cassone A, Torosantucci A. Antibeta-glucan antibodies in healthy human subjects. Vaccine 2009; 27:2513–2519.
125. Sandini S, La Valle R, Deaglio S, Malavasi F, Cassone A, De Bernardis F. A highly immunogenic recombinant and truncated protein of the secreted aspartic proteases family (rSap2t) of Candida albicans as a mucosal anticandidal vaccine. FEMS Immunol Med Microbiol 2011; 62:215–224.
126. Torosantucci A, Chiani P, Bromuro C, De Bernardis F, Palma AS, Liu Y, Mignogna G, et al. Protection by antibeta-glucan antibodies is associated with restricted beta-1,3 glucan binding specificity and inhibition of fungal growth and adherence. PLoS One 2009; 4:e5392.
127. Torosantucci A, Bromuro C, Chiani P, De Bernardis F, Berti F, Galli C, et al. A novel glyco-conjugate vaccine against fungal pathogens. J Exp Med 2005; 202:597–606.
128. Xin H, Dziadek S, Bundle DR, Cutler JE. Synthetic glycopeptide vaccines combining beta-mannan and peptide epitopes induce protection against candidiasis. Proc Natl Acad Sci U S A 2008; 105:13526–13531.
129. Spellberg BJ, Ibrahim AS, Avanesian V, Fu Y, Myers C, Phan QT, et al. Efficacy of the anti-Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J Infect Dis 2006; 194:256–260.
130. Lin L, Ibrahim AS, Xu X, Farber JM, Avanesian V, Baquir B, et al. Th1–Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog 2009; 5:e1000703.
131. De Bernardis F, Amacker M, Arancia S, Sandini S, Gremion C, Moser C, et al.A virosomal vaccine against candidal vaginitis: immunogenicity, efficacy and safety profile in animal models. Vaccine (submitted).
132. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection : causes and consequences. J Pathol 2008; 214:231–241.
133. Zelante T, Iannilli RG, De Luca A, Arroyo J, Blanco N, Servillo G, et al. Sensing of the mammalian IL-17 regulates fungal adaptation and virulence. Nat Com 2012; DOI 10.1038/ncomms 1085.

AIDS; Candida albicans; oropharyngeal candidiasis; pathogenesis; therapy; vaccines

© 2012 Lippincott Williams & Wilkins, Inc.