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

C.J.Carter

Flat 4, 20 Upper Maze Hill, St Leonard’s on Sea,  East Sussex, TN38 OLG

chris.john.carter@gmail.com

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Abstract

            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  V→I 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 (vatches) in the current virome that may be responsible for most of our ills. 

Intoduction

            The Human Immunodeficiency virus causes acquired immune deficiency syndrome (AIDS) by decreasing the capacity of the immune system to deal with opportunistic pathogens ⁵⁴. The virus infects and kills CD4+ T-Lymphocytes which play an important role in regulation of immune defence ³ and also targets B cells, 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 Fig 1. Homology of autoantigens with HIV-1 proteins from various autoimmune diseases is shown in Table 11 and Fig 1.

            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 RNA/DNA (i.e. viral) binding.  Homology to a thyroid hormone transporter was also observed. Thyroid hormones play an important role in preventing the decline in T- and B-cell efficiency in ageing ^15,30.

            Autoantigens from all the autoimmune disorders tested, Alzheimer’s disease, chronic obstructive pulmonary disorder, multiple sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Sjogrens syndrome and systemic Lupus Erythematosus are homologous to HIV-1 proteins (Table 11) and the homology searches detected two more involved in epidermolysis bullosa acquisita and systemic sclerosis.

             The antigenicity of these matching peptides, as indexed by the B-Cell Epitope prediction index ⁶⁴  is shown in Figs 2 and 3. Most are above the cut-off level of 0.35 set as default by the BepiPred server, suggesting that cross-reactivity between human and viral homologues is likely.

            Other viral infections have been implicated in a number of autoimmune disorders. The autoantigens in these disorders align with the respective viral risk factors (Table 12) and with many others, including phages infecting commensal bacteria, suggesting many potential viral contributors to autoimmune problems in a variety of disorders. The mutant proteins in Huntington’s disease and other polyglutamine repeat disorders as well as in cystic fibrosis also align with common viruses and phages (Table 12). The APP ₇₁₇  London mutation in Alzheimer’s disease ³⁹ is within a peptide liberated by beta- and gamma-secretase cleavage of APP as shown in Fig 4 ¹⁸. The native APP form of this peptide is itself homologous to several viruses and phages, but the mutation converts the peptide to one matching over 30 strains of rhinoviruses that cause the common cold, as well as many strains of the Norovirus that is a frequent cause of vomiting sickness (Table 13).

            Glycoprotein B of the Herpes simplex virus (HSV-1),  shows homology to beta-amyloid, exactly matching a VGGVV c-terminal sequence ⁹³ that has been used as an epitope to label beta-amyloid in the Alzheimer’s disease brain  ¹⁰². This pentapeptide, per se, forms aggregates characterised by twisted ropes and banded fibrils ⁸¹. This is a characteristic of both beta-amyloid and of HSV-1 glycoprotein B peptide fragments containing this sequence. The viral glycoprotein B fragments form thioflavine T positive fibrils which accelerate beta-amyloid fibril formation, and are neurotoxic in cell culture ²².

            Autoantibodies to beta-amyloid are common in the ageing population and in Alzheimer’s disease ^90,111 As shown in Table 14, 69 viruses and phages contain this consensus VGGVV sequence, suggesting that Alzheimer’s disease may also be related to viral mimicry. HSV-1 and other Herpes viral infections have been implicated as risk factors in Alzheimer’s disease ^52,66 and HIV-1 is frequently associated with dementia with Alzheimer’s-related neuropathology ³². (See also Viral and other environmental risk factors in Alzheimer’s disease and Multiple Sclerosis )

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 HLA-antigens 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 beta-amyloid 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.

 Acknowledgements: Thanks to the numerous authors for reprints, to Oliver Chao and Nasire Mahmudi for finding others, and to Maria Jesus Martin at Uniprot and Tao Tao at NCBI for help with the mysteries of BLAST and Clustal alignment settings.

Table 1-10: Human proteins aligning with various  HIV-1 proteins as indicated in the header of each table. Accession numbers are provided together with the amino acids aligning with the HIV-1 protein. Gaps are represented by – and conserved (similar properties) amino acids by +.  The immune-related function for each human protein is also recorded where available. Gene symbols are in brackets after each definition. Proteins in bold show a mean antigenicity index of greater than the default value of 0.35 along their respective peptide matches (e.g. Fig 2).

Table 1: Human proteins aligning with the HIV-1 env protein.

Table 2: Human proteins aligning with the HIV-1 p15 protein (vpr).

Table 3: Human proteins aligning with the HIV-1 p27 protein (nef).

Table 4: Human proteins aligning with the HIV-1 p16 protein (vpu).

Table 5: Human proteins aligning with the HIV-1 p19 protein (rev).

Table 6: Human proteins aligning with the HIV-1 p14 protein (tat).

Table 7: Human proteins aligning with the HIV-1 p23 protein (vif).

Table 8: Human proteins aligning with the HIV-1 gag-pol protein.

Table 9: Human proteins aligning with the HIV-1 gag protein.

Table 10: Human proteins aligning with the HIV-1 gp120 protein.

Table 11 Autoantigens from human autoimmune disorders showing significant homology to HIV-1 proteins

VGGVV

GYEVH—K

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 APP₇₁₇ 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.

Native

I

A

T

V

I

V 

I

T

L

V

Bacillus Phage NP_046589

Rabies virus ACN38519

Salmonella Phage YP_001742070

Sendai Virus BAC79139

*

*

*

*

*

Aeromonas Phage YP_238915

Enterobacteria phage AC14704

Human Coronavirus 229E CAA49377

Mossman Virus NP_958055

Pseudomonas phage YP_418190

SARS Coronavirus ACZ71766

*

*

*

*

*

Staphylococcus phage 

*

*

*

*

*

*

Aeromonas phage NP_932517, 

Flavobacterium Phage YP_112527

Mycobacterium Phage YP_002242149

Salmonella phages: Pseudocowpox ADC53802

Uncultured Phage 

*

*

*

*

*

Lactococcus Phage P_002875673

Pseudomonas Phage YP_003422512

Ralstonia Phage YP_001165297

Newcastle Disease virus ACZ72939

*

*

*

*

*

Human herpesvirus 5 (Cytomegalovirus) AAS48926

*

*

*

*

*

SARS coronavirus AAY60778

Burkholderia phage YP_001111213 

Enterobacteria phageYP_001837048

Human rotavirus A BAF95721

Human parainfluenza virus ACZ95446

Human adenovirus 1 AP_000521

Lactate dehydrogenase-elevating virus NP_042576    

*

*

*

*

*

Mutant

I

A

T

V

I

I 

I

T

L

V

Rhinovirus 50 ACK37391 and >30 other Rhinovirus strains

*

*

*

I

*

*

*

Virus PK224 ADF80719

Aeromonas phage NP_943894

Enterobacteria phage SP  ACY07251

Enterobacteria phage F1 NP_695026 (and others)

Listeria phage YP_002261439

Acanthamoeba polyphagamimivirus YP_001427182

SARS coronavirus AAU93319

*

*

*

I

*

Vaccinia Virus NP_048189

*

*

I

*

*

*

*

*

*

*

*

I

*

Human parainfluenza virus 1 CAA26576

*

*

*

*

I

Salmonella phage YP_003090232

*

*

I

*

*

*

*

*

I

*

*

Escherichia Phage YP_002003667

Bacillus phage S NP_690718

Mumps Virus AAD56373

GB virus A NP_045010

*

I

*

*

*

I

*

*

*

*

Table 14: Virus and phage proteins containing the VGGVV sequence, and the diseases they cause. Accession numbers are provided and seroprevalence is recorded for human viruses where available.

Enterobacteria phage

tail length tape measure protein

Prochlorococcus phage

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Figure 1:

The immune network localisation of the human proteins showing homology with HIV-1 proteins

β and γ) cleavage sites (­). The beta-amyloid sequence is highlighted in grey. The peptide used for homology searches is underlined.

...LTNIKTEEISEVKM­βDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVγ­IATVIV717ITLVM­γLKKK...

Mutation: V®I