[Frontiers in Bioscience E3, 1385-1400, June 1, 2011]

Charting the peptide crossreactome between HIV-1 and the human proteome

Guglielmo Lucchese1, Angela Stufano1, Michele Calabro1, Darja Kanduc1

1Department of Biochemistry and Molecular Biology,Ernesto Quagliariello, University of Bari, Bari, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Methods
4. Results 4.1. Theoretical and empirical values of the viral versus human heptapeptide overlap
4.2. Quantifying the immune cross-reactivity risk between HIV-1 and human proteins
4.3. Analyzing the pathologies potentially associated to HIV-1 cross-reactivity
4.3.1. HIV-1 heptapeptide cross-reactivity and immunosuppression.
4.3.2. HIV-1 heptapeptide cross-reactivity and neurological disorders.
4.3.3. HIV-1 heptapeptide cross-reactivity and muscle diseases.
4.3.4. HIV-1 heptapeptide cross-reactivity and malignancies.
4.3.5. HIV-1 cross-reactivity and other AIDS disorders: lipodystrophies, diarrhea, bone loss, corneal alterations, kidney disease, hypertension.
4.4. Analyzing sequence similarity of HIV-1 polyprotein to the human proteome at the pentapeptide level.
5. Discussion
6. Contributions
7. References

1. ABSTRACT

This paper defines potential peptide cross-reactivity between HIV-1 and the human host. Specifically, the amino acid primary sequence of HIV-1, isolate CDC-451, was analyzed for potential immunopathological relationships with the human proteome. The results revealed that: 1) HIV-1 shares 50 heptapeptides and three octapeptides with the human proteome; 2) 34 of the 50 shared heptapeptides are experimentally validated epitopes targeted by immune responses following HIV-1 infection; 3) the viral heptapeptide epitopes are present in human proteins that, when altered, are associated with disease characteristics of acquired immunodeficiency syndrome (AIDS) such as CD4+ cell loss, encephalopathy, schizophrenia, myopathy, cardiovascular disorders, hypertension, corneal diseases, diarrhea, lymphoma, and bladder cancer; 4) at the pentapeptide level, the viral-versus-human overlap is extensive (14,227 matches), with the viral pentapeptides disseminated throughout 10,312 human proteins. The findings are discussed in relationship to HIV-1 escape from immune surveillance, adjuvant-induced HIV-1 immunogenicity, autoimmune cross-reactions following human hyperimmune responses against HIV-1, and AIDS.

2. INTRODUCTION

During recent decades, many studies have focused on the existence of extensive sequence similarity between HIV polyprotein and human proteins, including the sequence similarity between HIV envelope and neuroleukin protein (1), the numerous peptide similarities between HIV proteins and nuclear antigens, such as the 70 kDa component of RNP particles involved in mixed connective tissue disease, and the centromere CENP-B protein, related to scleroderma (2,3), the structural similarity between a HIV-1 sequence overlapping env gp41 and selenium-dependent glutathione peroxidases (4), and the significant sequence similarity between a HIV-1 encoded peptide and the DNA binding loop of nuclear factor kappa B, known to bind thioredoxin (5). Accordingly, HIV pathogenesis has been causally associated with such peptide sharing (i.e., with autoimmune phenomena due to molecular mimicry between viral and host proteins) (6-11). Neuropathogenesis (1, 12), subversion of the immune system (13), autoimmune thyroid disease (14), and immunologic thrombocytopenia (15, 16) are HIV-related pathologies that have been causally linked to molecular mimicry (8-10, 17). However, despite the numerous studies, any link between HIV pathogenesis and HIV-induced immune response remains unclear. Moreover, currently, there is an enhanced effort in the clinical search for anti-HIV vaccines to be used in the prevention and therapy of HIV infection, notwithstanding the concern of inducing collateral autoimmune phenomena through cross reactions with the host proteome. A report of cardiolipin polyspecific autoreactivity by two broadly neutralizing HIV-1 antibodies is an example of such crossreactivity (18), and warns against indiscriminate immune-based approaches.

With the availability of the human proteome and access to public databases, we have examined the issue of HIV and molecular mimicry by a sequence-to-sequence analysis of viral versus human proteomes. Specifically, the current study addressed the following questions: i) How many human proteins harbor HIV peptide modules? ii) Can the potential cross-reactive risk between HIV-1 and Homo sapiens proteomes be quantified? iii) Based on peptide sharing data, might a relationship be drawn between viral-versus-human peptide sharing and HIV-induced AIDS?

3. METHODS

We used a HIV-1 sequence derived from an infectious clone of the US isolate CDC-451 as an experimental model. The HIV-1 sequence (Taxonomic Identifier: 11687, group M, subtype B, isolate CDC-451, polyprotein length: 1,682 aa) consisted of six proteins. Viral proteins, abbreviations, length, and UniProtKB/Swiss-Prot accession numbers are as follows: 1) Gag polyprotein, Gag, 500 aa (P05887-1), 2) Protein Vpr, viral protein R, 16 aa, (P05953), 3) protein Tat, transactivating regulatory protein, 101 aa (P05907), 4) Protein Rev, regulator of expression of viral proteins, 116 aa (P05865), 5) Protein Vpu, viral protein U, 81 aa (P08803), and 6) Envelope glycoprotein gp160, Env polyprotein, 868 aa (P05879).

The HIV-1 polyprotein sequence was dissected into 1,676 heptapeptides overlapped by six residues, i.e., they were each offset by one residue: MGARASV, GARASVL, ARASVLS, etc.Then, each viral heptapeptide was analyzed for exact matches with the human proteome using the Protein Information Resource perfect match program (pir.georgetown.edu/pirwww/search/peptide.shtml). The same procedure was applied when pentapeptides were used as probes in the matching analysis.

The human proteome consisted of 36,103 proteins and 15,697,964 occurrences of 10,431,975 unique 7-mers (20) at the time of analysis. Viral epitopes, functions of human proteins involved in the viral heptapeptide overlap, and potential disease associations were explored using the following publicly available resources: the HIV Molecular Immunology Database (http://www.hiv.lanl.gov/content/immunology), Universal Protein Resource (http://uniprot.org/uniprot), and PubMed (http://www.ncbi.nlm.nih.gov/omim).

4. RESULTS

In exploring the peptide commonality between HIV-1 and human proteins, as a first step, we carried out a systematic sequence-to-sequence peptide matching analysis of the viral polyprotein versus the human proteome at the heptapeptide level to quantitatively define the viral-versus-human overlap. Then, we searched the HIV Molecular Immunology Database (http://www.hiv.lanl.gov/content/immunology) for data on the immunoreactivity of the shared peptides to quantify the potential HIV-1 cross-reactivity risk in human immune responses. Finally, we analyzed the possible pathological impact of potential heptapeptide crossreactivity by examining the functional relevance of the human proteins involved in the viral epitope overlap. Table 1 presents the data obtained.

4.1. Theoretical and empirical values of the viral versus human heptapeptide overlap

Table 1 shows that HIV-1 shares 50 heptapeptides and three octapeptides with the human proteome, with a total of 52 human proteins involved in the overlap. As an immediate observation, the quantitation of the HIV-versus-human peptide overlap reveals a non-random nature of peptide sharing. Indeed, the human proteome is formed by 10,431,975 unique heptamers and 10,797,988 unique octamers, whereas the HIV proteome under analysis is formed by 1,676 unique heptamers and 1,675 unique octamers. Given 20 amino acids and the fact that amino acid composition has little or no effect on peptide frequencies (21), the theoretical probability p of a sequence of n amino acids occurring at random in two proteomes is 20-n multiplied by the n-mers in the two proteomes, according to the equation: p = 20-n x the number of unique n-mers comprising the viral proteome x the number of unique n-mers comprising the human proteome.

Thus, the number of times a given viral 7- or 8-mer might occur at random in the human proteome (calculated on the basis of the unique viral and human 7- and 8-mers) is 13.6 and 0.7, respectively. Therefore, the measured extent of overlap (50 heptapeptides and three octapeptides) reported in Table 1 is roughly 3.7- and 4.3-fold higher, respectively, when compared with the theoretically expected values.

4.2. Quantifying the immune cross-reactivity risk between HIV-1 and human proteins

Following the numerical quantitation of the HIV-1-vs-human peptide overlap, we tried to quantify the potential immune cross-reactivity risk by asking whether the peptides shared between HIV-1 and the human proteins were endowed with immunoreactive potential. Specifically, we searched the HIV Molecular Immunology Database (http://www.hiv.lanl.gov/content/immunology) for experimentally validated epitope data. We found that 35 of the 50 shared heptapeptides were located in (or are) epitopes targeted by human humoral and/or cellular immune response(s) following HIV-1 infection. The viral epitopes are reported in Table 1 as heptapeptide sequences shown in boldface (22-92).

4.3. Analyzing the pathologies potentially associated to HIV-1 cross-reactivity

As a final step, we undertook a functional analysis of the human proteins hosting the viral heptapeptide epitopes (last column in Table 1, entries in boldface). We found that, in general, the potential cross-reactivity risk related to the viral-versus-human epitopic peptide commonalities reported in Table 1 defines typical pathologies that occur in the course of HIV infection, such as immunosuppression, neurological disorders, myopathies, lipodystrophia, and malignancies.

4.3.1. HIV-1 heptapeptide cross-reactivity and immunosuppression

In addition to the well-known PEPTAPP peptide shared between HIV-1 Gag-Pol protein and the human T cell surface glycoprotein CD5 (26, 31, 61-63), a receptor that regulates T cell proliferation, we found the following cross-reactivities. 1) The Rev71-77VPLQLPP epitope is present in human Rho GTPase-activating protein 5. Rho GTPases have an essential role in human T cell development (93) and, clearly, a cross-immune reaction may contribute to destroying T cells. 2) The same observation holds for the occurrence of the Rev74-80QLPPLER epitope in the human activating molecule in BECN1-regulated autophagy protein 1, a protein involved in the control of T cell homeostasis (94). 3) The Env gp160303-310VEINCTR epitope is present in the human tumor necrosis factor receptor, also called CD95 (82). CD95 is expressed on CD4+, CD8+ and B cells. It is worth underlining that CD95, isoform 6, can block apoptosis.

It is logical to argue that altogether, immune cross-reactions with the above described T cell-related proteins may contribute to T cell loss and the consequent immunodeficiency characterizing HIV infection. Moreover, the Gag-Pol99-105ALDKIEE sequence is present in leucine-rich repeat flightless-interacting protein 2, which positively regulates cytokine production in macrophages (95). Cross-reactivity with LRRFIP2 following virus infection might contribute to reducing host defenses, thus adding to AIDS-associated immunosuppression. Immunodeficiency might also be enhanced by an immune hit on the C4a anaphylatoxin complement, hosting the Rev38-44RRNRRRR epitope, because alterations of CO4A are involved in inflammatory processes and primary immunodeficiency diseases (96).

4.3.2. HIV-1 heptapeptide cross-reactivity and neurological disorders

The Gag-Pol94-100RDTKEAL epitopic sequence occurs in the human striatin protein and might explain the frequency of comorbid HIV infection and schizophrenia (97). In fact, striatin is preferentially expressed in brain neurons and may play a role in dendritic Ca2+ signaling (98). Of relevance, a prefrontal cortex shotgun proteome analysis revealed altered calcium homeostasis and immune system imbalance in schizophrenia, with striatin showing statistically significant differential expression (99). Moreover, striatin is involved in the activation of endothelial NO synthase (100). Hence, the alteration of striatin may also prevent NO formation, thus underlying the association between HIV infection and stiffness of the common carotid artery (101).

Another possible link between immune activation and schizophrenia might be represented by the Env gp160270-276LLLNGSL epitope, which is common to the human dixin protein. Dixin is expressed ubiquitously, with higher expression in cardiac and skeletal muscles. Interestingly, dixin is a critical regulator of DISC1, the alteration of which has been associated with schizophrenia (102).

Neurological disorders might be related to potential cross-reactivity due to the presence of two consecutive overlapping viral epitopes, i.e., the Gag-Pol291-298PFRDYVDR octapeptide in the human copine 5 protein. Copine 5 is expressed in both neural progenitor cells and in differentiated neurons during neural development, suggesting a role for CPNE5 in the development of the central nervous system (103). Alterations in CPNE5 might underlie the cognitive delay and the course of HIV-1-associated progressive encephalopathy in children (104, 105).

Env gp160245-261NGTGPCT is found in the human leucine-rich repeat transmembrane neuronal protein 3 (LRTM3). In addition to a role in the development and maintenance of the vertebrate nervous system, LRTM3 is expressed almost exclusively in the nervous system, including regions affected during Alzheimer's disease, such as the dentate gyrus (106). An immune attack targeting the NGTGPCT sequence may determine inflammatory reactions at sites anatomically related to Alzheimer's disease, thus representing a pathogenic mechanism underlying the emerging intersection of HIV infection and Alzheimer's disease (107).

A potential neurological burden might be aggravated by the sharing of the Gag-Pol487-493SLRSLFG epitope with the human kinesin-like protein KIF1B, isoform 2, expressed abundantly in the brain. It is worth recalling that the down-regulation of KIF1B has been associated specifically with sporadic amyotrophic lateral sclerosis (108). Thus, an immune reaction against KIF1B might underlie the suggested association between HIV and sporadic amyotrophic lateral sclerosis (109-111). Also, the Tat49-55RKKRRQR epitope might play a role in amyotrophic lateral sclerosis because it is shared with the sodium channel protein type 3 subunit alpha, a protein that mediates the voltage-dependent sodium ion permeability of excitable membranes (112). Also, motor neuron disorders might be associated with the cross-reactivity derived from the presence of the Gag-Pol156-162KVIEEKA epitope in the regulator of G-protein signaling 17, a protein that inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits and is expressed predominantly in the cerebellum, cortex, and medulla. Alterations in GTPase activity have been related not only to amyotrophic lateral sclerosis (113), but also to malignancies. Indeed, neurofibromin 1 protein and tuberous sclerosis tumor suppressor complex regulate GTPase activities (114-116).

4.3.3. HIV-1 heptapeptide cross-reactivity and muscle diseases

Cross-reactivity between HIV and human ankyrin repeat domain containing protein occurs through the Gag-Pol302-308TLRAEQA epitope. Alterations of ankyrin repeat domain-containing proteins are involved in muscle diseases (117), and may be a cause of HIV-associated myopathies (118). A role in myopathy genesis following HIV-1 infection might also be played by immune activation against the Env gp160549-555LTVQARQ epitope, which is shared with the human AHNAK2, a protein that interacts with dysferlin. In dysferlinopathies, the reduction or absence of dysferlin is correlated with a secondary muscle-specific loss of AHNAK (119).

4.3.4. HIV-1 heptapeptide cross-reactivity and malignancies.

Regarding HIV-associated malignancies, potential cross-reactions might relate to the following matches: 1) the Gag-Pol285-292RQGPKEP epitope is shared with the human pre-B-cell leukemia transcription factor-interacting protein 1, which can inhibit the transcriptional activation of the oncogene E2A-Pbx (120); 2) the Gag-Pol14-20RWEKIRL epitope is present in the human "deleted in bladder cancer protein 1" (DBC1). This sharing fits with recent reports that bladder cancer can be added to the list of cancers that may be encountered in patients living longer with chronic HIV infection (121); 3) Env gp160209-215TSVITQA is present in the human cAMP-dependent transcription factor ATF-7, which binds the cAMP response element (consensus: 5'-GTGACGT(AG)(AG)-3'), a sequence present in many viral and cellular promoters. Moreover, it mediates the transcriptional activation exerted by the adenovirus oncoprotein E1 (122). ATF-7 is thought to support gene silencing by inducing histone H3-K9 trimethylation and may have a critical role in gene expression induced by social isolation stress (123); 4) the Env gp160280-286EVVIRSE epitope is shared with the human tumor suppressor retinoblastoma-like protein 1, also known as p107, a protein with a critical role in suppressing tumor progression (124, 125).

4.3.5. HIV-1 cross-reactivity and other AIDS disorders: lipodystrophies, diarrhea, bone loss, corneal alterations, kidney disease, hypertension

The Gag-Pol122-128GNSSQVS epitope is present in a human peroxisomal enzyme, 3-ketoacyl-CoA thiolase. Dysregulation of peroxisome function appears to be associated with the spectrum of biochemical changes seen in HIV associated lipodystrophies (126). Alterations in lipid metabolism might also derive from a cross-reaction between Env gp160489-495NWRSELY and the human acyl-coenzyme A thioesterase 4, a protein that catalyzes the hydrolysis of acyl-CoAs into the free fatty acid and coenzyme A, so regulating the intracellular levels of acyl-CoAs, free fatty acids, and coenzyme A.

The Gag-Pol124-130SSQVSQN epitope is present in the human intestinal guanylate cyclase C protein. This match may be of importance in AIDS syndrome, in light of two observations: 1) the binding of heat-stable enterotoxins to the intestinal receptor guanylyl cyclase C activates guanylyl cyclase and catalyzes the formation of cGMP, initiating a signaling cascade that opens the cystic fibrosis transmembrane conductance regulator chloride channel at the apical cell surface, thus causing secretory diarrhea, a leading cause of infectious diarrhea in humans (127). Thus, a HIV infection-induced humoral immune response targeting the SSQVSQN sequence may indicate the activation of guanylyl cyclase C and subsequent activation of the signaling cascade, leading to the secretory diarrhea status affecting HIV infected individuals (128, 129).

The Gag-Pol216-222PVHAGPI peptide epitope is present in the human receptor-type tyrosine-protein phosphatase epsilon (PTPRE), a protein that regulates osteoclast formation (129). Cross-reactivity with PTPRE might relate to HIV-associated bone loss and alterations (130, 131).

Two consecutive overlapping viral epitopes, in the Gag-Pol335-342ALGPAATL octapeptide, are present in the human transforming growth factor-beta-induced protein ig-h3 (BIGH3). This adhesion protein binds to type I, II, and IV collagens and is expressed highly in the corneal epithelium. Defects in BIGH3 cause corneal dystrophies (132). A cross-reaction with BIGH3 may underlie corneal alterations associated to HIV infection (133-135).

Cross reactivity between Rev103-109LVESPAV and the human polycystic kidney disease 1 protein might contribute to one of the primary comorbid conditions affecting HIV-infected individuals, chronic kidney disease (136).

Env gp160794-800VELLGRR is shared with a glucose transporter, GLUT-5, that functions primarily as a fructose transporter. Alterations of GLUT-5 are related to hypertension (137). Cross-reaction with GLUT-5 might contribute to the hypertension associated to HIV infection (138-141).

4.4. Analyzing sequence similarity of HIV-1 polyprotein to the human proteome at the pentapeptide level

We further analyzed the sequence similarity between the HIV polyprotein primary sequence and the human proteome to evaluate precisely the potential immunological cross-reactivity between viral and human proteins. To this aim, we used pentapeptides as scanning units. In fact, analyzing the sequence similarity between biological sequences in the immunological context equates to identifying the number of aligned epitopes with perfect sequence matching. In this case, immunological similarity analyses must consider the minimal length of an epitopic sequence (142, 143). As long ago as 1939, Landsteiner and van der Scheer demonstrated that a grouping of five amino acids could be an antigenic determinant (144). Since then, a number of scientific reports have validated five or six amino acids as the minimum size of the epitopic space characterizing humoral and cellular immune responses (147-151; reviewed in 152, 153), also exemplified by the HIV epitopes reported by Fiebig et al. (148). Based on these experimental reports, we defined immune epitopic peptide units as pentapeptides (143).

Thus, with the aim of obtaining a better definition of the potential cross-reactivity between HIV and the human host, the HIV-1 polyprotein sequence under analysis was dissected into 1,678 pentapeptides, each offset by one residue. Each viral pentapeptide was then used as a probe to scan the entire human proteome, searching for perfect matches. The data we obtained are presented in Figure 1, showing the number of matches with the human proteome for each HIV-1 pentapeptide and clearly documenting the existence of a massive viral-versus-human pentapeptide overlap. The pentapeptide identity profile of the HIV-1 polyprotein primary sequence versus the human proteome (i.e., the number of times each HIV-1 pentapeptide is present in the human proteome) exhibits a range of behavior, with some HIV-1 polyprotein areas formed by pentapeptides matching a low number of human proteins, while others are formed by pentapeptides recurring in many different human proteins. As an example, the HIV-1 Env gp160675-679LDKWA pentapeptide matches only a single human protein (kynureninase, UniProtKB/Swiss-Prot accession: D3DP79), whereas the HIV-1 Env gp160 671-675ELLQL pentapeptide occurs in 68 different human proteins. In parallel, multiple viral occurrences can also occur in the human proteins (e.g., human titin shares 35 pentapeptides with HIV-1).

A snapshot of the HIV pentapeptide overlapping with the human proteome is reported in Table 2. Numerically, the viral 5-mers occurring in the human proteome (including multiple occurrences) amount to 14,227 and include proteins associated with the most crucial functions of the cell, from proliferation to apoptosis, from immune regulation to enzyme activity. Theoretically, the number of times a given pentamer from HIV-1 (isolate CDC-451, polyprotein length 1,682 aa) might occur at random in the human proteome (as calculated on the basis of the unique viral and human 5-mers) is 1,252. Therefore, the extent of overlap (14,227 matches) reported in Table 2 is roughly 11-fold higher than the expected value. Similar data were obtained by analyzing HIV-1, Taxonomy ID 11676 (data not shown).

The human proteins hosting HIV-1 pentapeptide(s) are listed in Table 3 (see Supplemental Data).

5. DISCUSSION

The current study demonstrated that: 1) HIV-1, isolate CDC-451, shares numerous perfect heptapeptide matches with human proteins; 2) most of the shared heptapeptides are part of epitopes immunologically recognized by a human immune response(s) following HIV-infection (i.e., they have immune potential), and 3) the viral epitopes are present in human proteins that, when altered, are related to diseases characteristic of HIV-associated AIDS.

These data suggest that the constellation of diseases associated with HIV-infection may be related to anti-HIV immune responses. This hypothesis is supported by a pioneering study by Martinez et al. (154), who observed that AIDS-associated immunosuppression might be due to human anti-HIV immune responses, rather than to the pathogenicity of the virus. It was suggested that the basis of the immunosuppression could be molecular mimicries involving viral gp-110, CD4 molecules, antibodies, and CD4-acceptor sites. As a conclusion, the study remarked on the advantage of being a low responder subject (i.e., a low producer of potentially harmful autoantibodies), and warned that anti-HIV vaccination might protect against infection but, at the same time, cause immunosuppression and disease. Using the current databases, our study scientifically validates the reasoning of Martinez et al. Successively, Victorino's group (155) reached a similar conclusion by comparing several immunological and viral variables during HIV-1 and HIV-2 infection, and found that immune activation, and not viremia, is closely linked to the extent of CD4 depletion in both infections.

Additionally, the current study provides a detailed picture of the phenetic commonalities between a HIV-1 strain and the human host. As discussed in the Introduction, numerous studies on the HIV-versus-human sequence similarity and potential cross-reactivity have been reported (1-18, 20, 61, 62). Here, using the immune pentapeptide unit, we report for the first time a complete immune cross-reactivity map between HIV-1 and the human proteome. The present study demonstrates that the HIV-1 polyprotein analyzed presents thousands of pentapeptides (14,227) disseminated widely and repeatedly throughout the human proteome. Moreover, the human proteins involved in the viral overlap amount to 10,312; that is, about 32% of the human proteome contains viral pentamers. The implications of these data are profound, because pentapeptides are the minimal biological units exerting roles in immunobiology (151, 152). De facto, given the extent of the pentapeptide identity pattern between HIV-1 and humans, clearly, an anti-HIV immune response may explain the wide spectrum of autoimmune disease, as well as the complex array of autoantibodies towards the most disparate human targets in HIV/AIDS (156), definitely supporting the link described in Table 1 between the (auto)immune activation caused by HIV infection and AIDS.

However, the pentapeptide identity pattern between HIV-1 and humans poses the following unavoidable crucial question: what triggers the anti-HIV immune response in the high-responders HIV-infected subjects? As a matter of fact, when high degrees of immunological similarity (i.e., identity at the level of immunobiological units) are present between microbial organisms and humans, the breaking of the immunotolerance mechanisms that avoid harmful self reactivity seems unlikely, because the sharing of epitopes with the host's molecules may rather represent an elective microbial mechanism to escape immune surveillance (157, 158). In fact, we and others (19, 20, 159, 160) have demonstrated that a number of viral proteomes, independent of their structural or pathogenic characteristics, present a high number of pentapeptide overlaps with the human proteome (19, 20) and, likewise, bacterial peptides are present throughout the human proteome (159, 160). As a logical conclusion, Kanduc (143, 161, 162) argued that the peptide identity platform unifying microbes and humans is at the root of the immune escape phenomenon (i.e., the root of what the immunologists call the enigma of successful viral/bacterial escape from immune surveillance) (163-165). According to the relationship of high similarity-immune escape advocated by Kanduc (143, 162), vaccines containing the infectious agent are generally ineffective because they have scarce or no immunogenicity. To induce/increase an immune response, as a rule, vaccinology uses adjuvants (166), a highly heterogeneous group of chemical compounds which, through mechanisms not yet clear, bypass the host immunotolerance mechanisms and elicit hyperactivation of the immune system. Currently, aluminum salts and aluminum hydroxide are the most powerful (and used) adjuvants.

Consequently, to determine what triggers the anti-HIV immune response in the high-responders to the HIV-infection, we cannot help to recall that aluminum hydroxide has many applications in pharmaceuticals. In particular, it is an antacid, as well as an approved protectant used to heal and protect minor wounds, skin abrasions, skin tears and partial thickness pressure ulcers, and a component par excellence of ointments for treatment of hemorrhoids and nonhemorrhoidal anorectal conditions (such as fissure, abscess, skin tags, rectal prolapse, or pruritus ani) (167). In this regard, epidemiological studies aimed at analyzing a possible link between the use of aluminum-based compounds and immune activation following HIV infection are warranted. Also, the adjuvant action exerted by bacterial lipopolysaccharides (LPSs) has to be considered. LPSs act as adjuvants by inhibiting the induction of tolerance by nonimmunogenic tolerogenic antigens (168). Likewise, it is well known that bacteria are also frequent concomitant pathogens to HIV infection (169) and have been implicated in promoting HIV-1 pathogenesis through bacterial LPSs (170, 171). To conclude, it seems that the immune hyperactivation against the high-similarity tolerogenic HIV polyprotein and the successive progression to AIDS in specific cohorts of HIV-infected individuals might be specifically related to the presence of adjuvants of bacterial and/or chemical nature. Of note, our considerations would explain the highly context-dependent progression of HIV/AIDS and its secondary complications among patients (172-176).

Finally, this study joins other reports (18, 61) in suggesting that HIV antigen-based vaccines might have harmful outcomes in the prevention or treatment of HIV infection, and further supports Kanduc's suggestion (177, 178) that only epitopic peptides with low similarity to the human proteome may offer a basis for rational anti-HIV vaccines avoiding collateral adverse events (179, 180).

6. CONTRIBUTIONS

GL, AS, and MC have been involved in data analysis. DK conceived and designed the study, interpreted the data and wrote the manuscript. All authors have read and approved the final manuscript.

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Key Words: HIV-1 proteome, human proteome, HIV-vs-human crossreactome, HIV-derived epitopes, HIV escape from immune surveillance, adjuvant-induced immune activation, crossreactivity-induced AIDS

Send correspondence to: Darja Kanduc, Dept. of Biochemestry & Molecular Biology, University of Bari, Bari, Italy. Tel: 390805443321 Fax: 390805443317, E-mail:d.kanduc@biologia.uniba.it