Extensive Viral mimicry of human proteins in AIDS, autoimmune disorders, late-onset and familial Alzheimer's disease and other genetic diseases

Peptide stretches within HIV-1 proteins display homology to over 50 components from all compartments of the human immune defence network. The homologous peptides are in most cases immunogenic, suggesting that antibodies to HIV-1 proteins could mount an autoimmune attack against multiple components of the immune system itself. HIV-1 proteins are also homologous to autoantigens in Alzheimer's disease, chronic obstructive pulmonary disorder, multiple sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Sjogrens syndrome and systemic Lupus Erythematosus, all of which have been associated with HIV-1 infection. This mimicry suggests that HIV-1/AIDS has a major autoimmune component and that HIV-1 antibodies could selectively target the immune system and autoantigens in other autoimmune disorders. This could radically change our conception of how HIV-1 acts, and perhaps lead to novel therapeutic strategies, which, counter intuitively might even involve the use of immunosuppressants in the early stages of the disease. Autoantigens from the human autoimmune diseases mentioned above also align with peptides from other viruses implicated as risk factors in each disease. Mutant peptides from Huntington's disease and other polyglutamine disorders, and from cystic fibrosis also align with common viruses. The London APP717 VxI mutant in Familial Alzheimer's disease converts the surrounding peptide to matches with Rhinoviruses causing the common cold and to the Norovirus responsible for vomiting sickness. Viral mimicry related autoimmunity may thus play a role in many autoimmune and even human genetic disorders. It is possible that this is a near universal phenomenon, reflecting the idea that viruses are responsible for the origin of higher forms of life, leaving behind a deadly legacy of viral-derived human proteins with homology to antigenic proteins in the current virome that may be responsible for most of our ills.

natural killer cells, macrophages and microglia 115 . It has already been noted that the HIV-1 envelope protein is homologous to several components of the immune system including HLA antigens, T cell receptors, Fas and immunoglobulins G and A 109 and also that autoimmune disorders are common in HIV-infected patients (Sjogrens syndrome 59 rheumatic disease 74 and lupus 127 ) for example. HIV-1 has also been associated with myaesthenia gravis 83 multiple sclerosis 9 and pemphigus 49 and can worsen symptoms in chronic obstructive pulmonary disease 105 . HIV-1 infection can also cause dementia with Alzheimer's disease-like pathology 32 . These associations may be related to immune deficiency but could also reflect viral/antigen mimicry in these autoimmune disorders. Homology searches showed that all the autoantigens in these autoimmune diseases are homologous to short peptide stretches of diverse HIV-1 proteins, and that all HIV-1 proteins display this type of homology with important elements of the human immune and pathogen defence networks, suggesting that HIV-1 itself has an autoimmune component where antibodies to HIV-1 proteins may target crucial molecules within the immune system. This type of mimicry between viral and human proteins is observed for large number of other viruses, in most cases matching their reported implication in the relevant disease. It is common in many autoimmune disorders, and even in human genetic disorders where the mutant protein modifies the spectrum of viral matches to very common pathogens.

Methods
Homology searches, of HIV-1 proteins against human proteins and of human autoantigens against HIV-1 proteins were undertaken at the Uniprot BLAST server, using parameters designed to detect short consecutive peptide matches rather than overall homology 4 . B-Cell epitopes were identified using the BepiPred server http://www.cbs.dtu.dk/services/BepiPred, which predicts the B-cell antigenicity of peptide sequences 64 . Parameters were set to default (epitope predicted above an index of 0.35). Further homology searches were undertaken against all viral proteins in relation to autoantigens in autoimmune disorders and to mutant proteins in Alzheimer's disease, Huntinton's disease and other polyglutamine disorders and in cystic fibrosis.

Results
The homology search results for each HIV-1 protein are shown in Tables 1 to 10 and summarised in Fig 1. It should be noted that all homologues (consecutive pentapeptides or more, or greater than 85% similarity) are recorded in these tables and that homology (for known proteins) is restricted to the classes shown in the tables and As can clearly be seen from the data in the various tables and from Fig 1, HIV-1 proteins are homologous to human proteins from every compartment of the immune system, including HLA-antigens, B-and T-cells, natural killer and dendritic cells, as well as macrophages, microglia and mast cells, and lysosomes which destroy foreign antigens and pathogens 69,92 . A number of HIV-1 proteins are also homologous with proteins involved in haematopoiesis, which generates both red and white blood cells. Others are homologous to pathogen and pattern recognition pathways as well as to those implicated in responses to DNA damage, oxidative stress and to single stranded

Discussion.
All HIV-1 proteins show a high degree of homology to short peptide stretches of important proteins in most compartments of the immune system a phenomenon that is almost exclusively limited to proteins of the immune network. For the most part, these peptides are predicted to be highly immunogenic, suggesting that HIV-1/AIDS is an autoimmune disorder that targets a large and diverse spectrum of proteins in the immune and pathogen defence network. HIV-1 proteins are also homologous to autoantigens in a variety of autoimmune disorders that have been associated with HIV-1 infection. These homologous human proteins have important roles in almost every aspect of immune function (Fig 1) and autoantibodies to almost any would be expected to disrupt the immune network. Antibodies to T-cell receptors and HLAantigens have been reported in AIDS patients, along with many others, and a contribution of molecular mimicry and autoimmunity to AIDS pathogenesis has already been proposed 7,8,73,100,112 . This survey shows how extensive this process could be and demonstrates a very selective targeting of the immune network. Certain autoantibodies may be beneficial in AIDS 47 and other disorders, for example betaamyloid catalytic antibodies in Alzheimer's disease 90 . Certain proteins within this mimicry network are immunosuppressive, for example Sirtuin (Table 1), the Fc receptor FCGR2B (Table 3) and the homoeobox protein ALX1 (Table 5) while others  stimulate immune cell development or function, for example RET (table 2) CD226 (Table 6) and Plexin B1 (Table 7). There may be ways of exploiting these differences in the design of potential therapies, for example vaccination to raise beneficial autoantibodies against the immunosuppressant proteins, or anti-antibody antibodies targeting the immunostimulant proteins. While totally counter intuitive, immunosuppressive therapies could also be of benefit in the early stages of infection.
Autoantigens in a variety of autoimmune disorders are homologous to proteins from other viruses that have been implicated as risk factors and to others that have not been suspected. Late-onset Alzheimer's disease may also be added to the list of autoimmune disorders. Amyloid plaques in the brains of Alzheimer's disease patients contain a variety of immune-related proteins 28,29,119 and Alzheimer's disease neurones express the complement membrane attack complex, suggesting that complement related lysis as a response to beta-amyloid antigenicity may be responsible for neuronal death as already suggested 50,76 . .
Finally, even in human genetic disorders, including Huntington's disease, and spinocerebellar ataxias or cystic fibrosis, mutant proteins align with common viral proteins. The London mutation in Familial Alzheimer's disease converts the resultant peptide to one matching proteins from over 30 strains of Rhinovirus that cause the common cold, a potential unexpected cause of familial Alzheimer's disease. Many of these diseases have symptoms related to the altered function of the mutant protein.
Most have a degenerative component that could well be related to autoimmune attack triggered by complementary viral proteins, rather than to the mutant protein itself. Viral mimicry thus appears to be a universal phenomenon, that may be relevant to AIDS, autoimmune disorders, late-onset Alzheimer's disease and even human genetic disorders.
Phages and viruses are the simplest form of "life", as defined by the possession of DNA/RNA and a proteinaceous structure, and were long ago proposed as the origin of higher cellular organisms 23,45 . While they may well be responsible for our existence, they appear to have left behind a legacy of viral derived human proteins that are homologous to many current viral antigens. There are currently 2463 viral genomes in the NCBI database, likely representing but a small percentage of those existing, and the likelihood of antigenic mimicry must be proportionately extensive. Viral related autoimmunity may thus be relevant to a large number of human ailments, a situation that has therapeutic implications in many diseases of autoimmune, polygenic and genetic origin, where pathogen elimination, vaccination and immunosuppression may be of benefit. Antibody arrays on the same scale as genome-wide association studies may also be envisaged to identify the most common culprits in these disorders.     LGQH+Y-TY              Table 12 Viral proteins lining up with autoantigens from Chronic obstructive pulmonary disease, myasthenia gravis, multiple sclerosis, pemphigus vulgaris and lupus and to mutant proteins from polyglutamine repeat disorders (Huntington's disease, Dentatorubropallidoluysian atrophy, Kennedy disease and Spinocerebellar ataxias) and from cystic fibrosis. APOE4 is included as an example of a risk factor in a number of polygenic diseases. Accession numbers and the aligning sequences are shown with references where the virus has been implicated in the relevant disease. The polyglutamine expansions also increase the antigenicity of the resultant peptide with each triplet QQQ addition     Table 13 The effects of the London APP 717 mutation on homology to viral proteins. Protein accession numbers are provided and amino acid matches are indicated by the asterisks or by the red letter of the mutant amino acid. Phages infecting commensal bacteria and common viruses (eg Rhinoviruses and Norovirus) are highlighted in bold.   The B-cell epitope prediction profiles for the peptide matches between HIV-1 and human proteins. The prediction method calculates the antigenicity amino acid by amino acid allowing definition of the immunogenic spectrum along the length of the peptide 64 . Each bar within each set of histograms thus represents a single amino acid, derived from the alignments in tables 1 to 10. The default threshold predicting B-cell epitopes is 0.35. Fig 4: The localisation of the APP 717 London mutation and of the beta-and gamma-secretase (β and γ) cleavage sites (↑). The beta-amyloid sequence is highlighted in grey. The peptide used for homology searches is underlined.