Since the report by Klein et al. in 1984 , 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 . 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 . With all evidence, OPC and OEC have not ended in the ART era .
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.
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 . 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 (; see below).
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.
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 ). Hyphal development can be inhibited by farnesol, an autoregulatory compound, which inhibits Ras1–cAMP pathway .
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].
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.
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).
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 , 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  (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].
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 . 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 .
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 ) 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  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.
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 . Notably, these cells are expanded in the HIV-positive patients possibly as an attempt to fill the defensive gap generated by CD4 cell loss.
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 . 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).
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 . 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 .
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].
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.
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  and have generated interest in novel class of anticandidal drugs having Sap as a target .
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 , one of which affects HIV by co-receptor mimicry  (Table 5).
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 . 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 . 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.
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.
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 , 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. 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.
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’.
Conflicts of interest
There are no conflicts of interest.
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