BioMed Research International
Volume 2017 (2017), Article ID 7973165, 11 pages
https://doi.org/10.1155/2017/7973165

Review Article

Cooccurrences of Putative Endogenous Retrovirus-Associated Diseases

Christine Brütting,1,2 Alexander Emmer,² Malte E. Kornhuber,² and Martin S. Staege¹

¹Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Halle, Germany
²Department of Neurology, Martin Luther University Halle-Wittenberg, Halle, Germany

Correspondence should be addressed to Christine Brütting; christine.bruetting@uk-halle.de

Received 26 November 2016; Revised 21 January 2017; Accepted 6 February 2017; Published 23 February 2017

Academic Editor: Alex Greenwood

Copyright © 2017 Christine Brütting et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

At least 8% of the human genome is composed of endogenous retrovirus (ERV) sequences. ERVs play a role in placental morphogenesis and can sometimes protect the host against exogenous viruses. On the other hand, ERV reactivation has been found to be associated with different diseases, for example, multiple sclerosis (MS), schizophrenia, type 1 diabetes mellitus (T1D), or amyotrophic lateral sclerosis (ALS). Little is known about the cooccurrence of these diseases. If all these diseases are caused by ERV, antiretroviral therapy should perhaps also show some effects in the other diseases. Here, we summarize literature demonstrating that some ERV-associated diseases seem to appear together more often than expected, for example, MS and ALS, MS and T1D, MS and schizophrenia, or ALS and T1D. In contrast, some ERV-associated diseases seem to appear together less frequently than expected, for example, schizophrenia and T1D. Besides, some reports demonstrate amelioration of MS, ALS, or schizophrenia under antiretroviral therapy in human immunodeficiency virus-infected patients. If such results could be confirmed in larger studies, alternative therapy strategies for ERV-associated diseases like MS and schizophrenia might be possible.

1. Endogenous Retroviruses and Diseases

It is known that almost half of human DNA sequences belong to the group of repeated or (retro)transposable elements [1]. First discovered by McClintock in the 1950s [2], such sequences were considered as “junk” DNA for decades [3]. In the last years the perspective changed and retroelements are now seen as important drivers for species diversity [4] as well as possible factors in human diseases, especially in autoimmune diseases [5].

Endogenous retroviruses (ERV) have been detected in numerous eukaryotic organisms. Their exogenous counterparts have infected vertebrates including Homo sapiens [6]. At least 8% of the human genome is composed of endogenous retroviral sequences. These sequences were integrated into the human genome in the course of the evolution. The great majority of HERV are stabilized in the genome, but there is still ongoing or potential HERV genotype modification from parents to offspring throughout generations. As ERV are susceptible to mutations, the majority of ERV in our genome is not competent to replicate and most ERV sequences are presumably silent [7]. However, some of these sequences still have open reading frames (ORFs) and therefore have the potential to code for proteins or peptides [8, 9]. Oja and coworkers [10] found that about 7% of all ERV sequences in the human genome are transcriptionally active. ERV can be reactivated by some exogenous viruses like Epstein Barr virus (EBV), herpes simplex virus 1, or human immunodeficiency virus 1 [11–13]. Another possibility is the reactivation of ERV expression by hypoxia [14].

ERVs have also contributed to certain physiological genes through mutations and modifications that conferred physiologically important functions like placental morphogenesis [8] and can sometimes protect the host against infections with exogenous retroviruses [15]. On the other hand, ERV have also been found to be associated with different diseases [16, 17]. Our study addresses HERVs as being involved in the pathogenesis of chronic noninfectious diseases, for example, multiple sclerosis [18, 19], schizophrenia [20], type 1 diabetes mellitus [21], and amyotrophic lateral sclerosis [22] and, in parallel, as potential interfering factors when activated by infections with exogenous retroviruses such as HIV.

1.1. Multiple Sclerosis (MS)

Multiple sclerosis is a chronic immune-mediated inflammatory disease of the central nervous system with characteristic patchy demyelination. It is the most common chronic disabling CNS disease in young adults and affects about 2.3 million people around the world [23, 24]. The etiology of MS has not been completely decoded so far, supposing that causes are multifactorial including environmental influences [25] as well as epigenetic and genetic factors [26]. Family aggregation studies show that the general population prevalence of 0.1% [27] increases with the degree of kinship from 7–50-fold for biological first-degree relatives [28, 29] to a risk of about 300-fold for monozygotic twins [30, 31]. The impact of environmental factors on triggering of disease onset remains unclear. Sunlight exposure and resulting vitamin D levels [32] as well as EBV infection [33] are discussed.

Commonly an autoimmune attack against myelin autoantigens is considered as the main factor in the pathogenesis of MS [34, 35]. Additionally, HERVs are discussed to contribute to MS [36–38].

Several HERVs are considered to be involved in multiple sclerosis pathogenesis [39]. For example, the HERV-W env mRNA expression was selectively upregulated in brain tissue from individuals with multiple sclerosis as compared with controls [40].

1.2. Schizophrenia

Schizophrenia is a severe chronic psychiatric disorder characterized by “positive” symptoms like delusions and hallucinations as well as negative symptoms like blunted affect or emotional withdrawal [41]. Worldwide more than 23 million people suffer from schizophrenia [24]. The causes of schizophrenia are probably a mixture of genetic and environmental factors. The general population prevalence of about 1% increases with the degree of kinship from 6 to 13 % for biological first-degree relatives to a risk of 48% for monozygotic twins [42]. In addition to genetic factors, environmental factors like cannabis abuse [43] and urbanization [44] are discussed.

Schizophrenia seems to be associated with ERV. Elevated levels of multiple sclerosis-associated retrovirus (MSRV) and ERV-FRD sequences in the brains and cerebrospinal fluids of schizophrenia patients compared to healthy controls have been observed [45]. An increased transcription of HERV-W elements and the existence of antigens of HERV-W envelope and capsid proteins were found in blood samples from affected individuals [46]. In addition, a significantly higher HERV-K10 activity was detected in the brains of schizophrenia patients compared to healthy controls [47].

1.3. Type 1 Diabetes (T1D)

Type 1 diabetes is characterized by an autoimmune destruction of insulin producing beta cells in the pancreas which usually leads to absolute insulin deficiency [48]. It is one of the most common chronic diseases of childhood [49] although it can be diagnosed at any age. T1D has high and increasing worldwide prevalence rates with some regional variability [50]. Boys and men are more affected than girls and women [51]. The etiology of T1D is still unclear. Again, causes seem to be multifactorial including genetic factors like special HLA haplotypes [52] as well as environmental influences like vitamin D deficiency [53] and virus infections [54].

The association between T1D and endogenous retroviruses has been discussed controversially [55, 56]. There is some evidence for the association of HERV-K18 polymorphisms with T1D [57, 58]. Moreover, there seems to be a link between the retrovirus-like long-terminal repeat DQ-LTR13 and the genetic susceptibility to T1D [59].

1.4. Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the loss of spinal and cortical motor neurons [60]. It is an often rapidly progressive disease with a median survival of 3 years [61]. ALS has a prevalence of around 6 per 100,000 [62]. Men are a little bit more often affected than women with a male-female ratio of 1.5 to 1 [63]. Most cases of ALS (90–95%) are sporadic, only about 5–10% of ALS cases are familial [64]. In familial ALS various genes have been identified that are associated with the disease. Superoxide dismutase 1 (SOD1) is the most important of them, accounting for up to 20% of all familial ALS cases [65, 66].

For ALS there are some associations to ERV. HERV-K transcripts are increased in autopsy brain tissue of patients with ALS compared to controls [22] and antiretroviral seroreactivity in patients with sporadic ALS was found [67]. Thereby neuronal TAR DNA binding protein 43 (TDP-43) regulates endogenous retrovirus-K viral protein accumulation [68]. Expression of HERV-K or its envelope protein in human neurons caused retraction and beading of neurites [69]. This is also reproducible in transgenic mouse model: expressing the envelope gene of HERV-K leads to progressive motor neuron dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage [69].

1.5. Human Immunodeficiency Virus (HIV) Infection

HIV infection and acquired immune deficiency syndrome (AIDS) comprise a wide range of disorders and diseases caused by HIV, including tumors or opportunistic infections [70, 71]. Likely more than 35 million people around the world have been diagnosed with HIV [72]. Women are a little bit more often affected than men [73].

The HIV infection is a special case in our register of diseases that seem to be associated with ERV as HIV itself is a retrovirus. HIV can be divided into two virus subtypes (HIV-1 and HIV-2) which infect and kill CD4+ T lymphocytes [74]. The treatment consists of highly active antiretroviral therapy (HAART) which slows the progression of the disease and normally leads to a much higher life expectancy than without the therapy [75]. Interestingly, HIV infection seems to be associated with ERV reactivation. Vincendeau and coworkers [76] detected in three persistently HIV-1 infected cell lines an increased transcription of HERV-E, HERV-T, HERV-K, and ERV9. HERV-K102 is often activated in cases of HIV viremia in contrast to healthy controls [77]. Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1 [78, 79].

2. Cooccurrence of ERV-Associated Diseases

We searched the literature for cooccurrences of the diseases discussed above. Table 1 summarizes publications [80–157] that investigated such cooccurrences.

Table 1: Cooccurrence of diseases with possible involvement of ERV reactivation.

Number of cases
Association between diseases
Comments
Ref.

MS and schizophrenia

1
n.a.
Case report
[80]

2
n.a.
Case report
[81]

10
n.a.
Research study
[82]

1
n.a.
Case report
[83]

n.a.
Positive
Epidemiological investigation
[84]

3
No association
Population-based register study
[85]

1
n.a.
Case report
[86]

67
Positive
Population-based controlled study
[87]

63
Positive
Population-based register study
[88]

39
No association
Epidemiologic investigation
[89]

36
Negative
Population-based register study
[90]

MS and T1D

5
Positive
Population-based register study
[91]

3
n.a.
Clinical register study
[92]

1
No association
Clinical register study
[93]

28
Positive
Cohort study
[94]

n.a.
Positive
Clinical register study
[95]

11
Positive
Population-based cohort study
[96]

MS and ALS

1
n.a.
Case report
[97]

1
n.a.
Case report
[98]

1
n.a.
Case report
[99]

1
n.a.
Case report
[100]

1
n.a.
Case report
[101]

1
n.a.
Case report
[102]

1
n.a.
Research study
[103]

1
n.a.
Case report
[104]

1
n.a.
Case report
[105]

7
Positive
Epidemiologic investigation
[106]

143
Positive
Clinical register study
[107]

1
No association
Population-based case-control study
[108]

MS and HIV infection

1
n.a.
Case report
[109]

1
n.a.
Case report
[110]

1
No association
Population-based register study
[111]

1
n.a.
Case report
[112]

10
Negative
Comparative cohort study
[113]

1
n.a.
Case report
[114]

1
n.a.
Case report
[115]

Schizophrenia and T1D

0
Negative
Population-based register study
[116]

n.a.
No association
Population-based register study
[117]

24
No association
Population-based register study
[85]

24
Negative
Population-based register study
[118]

Schizophrenia and ALS

2
n.a.
Case report
[119]

1
n.a.
Case report
[120]

2
n.a.
Case report
[121]

1
n.a.
Case report
[122]

1
n.a.
Case report
[123]

2
n.a.
Case report
[124]

2
n.a.
Case report
[125]

2
n.a.
Case report
[126]

Schizophrenia and HIV infection

13
n.a.
Clinical register study
[127]

3
n.a.
Clinical cohort
[128]

8
n.a.
Cohort study
[129]

11
n.a.
Clinical cohort
[130]

10
n.a.
Clinical cohort
[131]

13
n.a.
Clinical cohort
[132]

1
n.a.
Clinical cohort
[133]

476
n.a.
Population-based register study
[134]

7
n.a.
Clinical cohort
[135]

11
n.a.
Clinical cohort
[136]

1
n.a.
Case report
[137]

28
n.a.
No data
[138]

68
Positive
Population-based cohort study
[139]

T1D and ALS

216
Positive
Clinical register study
[107]

43
No association
Population-based case-control study
[140]

T1D and HIV infection

1
n.a.
Case report
[141]

1
n.a.
Case report
[142]

1
n.a.
Case report
[143]

1
n.a.
Case report
[144]

1
n.a.
Case report
[145]

1
n.a.
Case report
[146]

1
n.a.
Case report
[147]

1
n.a.
Case report
[148]

7
n.a.
Clinical register study
[149]

3
n.a.
Case report
[150]

10
n.a.
Population-based register study
[151]

1
n.a.
Case report
[152]

ALS and HIV infection

1
n.a.
Case report
[153]

1
n.a.
Case report
[154]

1
n.a.
Retrospective hospital cohorts
[155]

1
n.a.
Case report
[156]

2
n.a.
Case report
[157]

Not available, not tested, or not presented in the publication.

The number of cases was not reported; the prevalence of psychotic disorders among more than 10,000 MS patients was reported as 1.3%.

The number of cases was inferred from incidence as presented in the publication; the number was not explicitly reported.

Not available; the number of patients was not reported.

No schizophrenia cases were found among 1,154 diabetics below 27 years of age.

Not available; the number of cases was not reported; the prevalence of psychoses among nearly 17,000 patients with T1D was reported as 0.8%.

Number of HIV positive patients developing schizophrenia.

2.1. MS and Schizophrenia

The cooccurrence of MS and schizophrenia has considered being a very rare event taking into account the few case reports in the literature [81, 82, 86]. Nevertheless, Jongen [83] suggested MS screening in patients with psychotic disorder even if only slight neurological abnormalities are present. The first epidemiologic evidence for a positive association between MS and schizophrenia was shown in a Canadian population including 2.45 million people [84]. This association was also found in Taiwanese [87] and Danish [88] patients with MS. In a nationwide Swedish cohort [90] and a Canadian population [89] there was an association between MS and bipolar disorders as well as between MS and depression; in contrast there was no or even a negative association between MS and schizophrenia. Also a Danish cohort study failed to find a positive association [85]. Another Danish cohort study found at least a higher risk for parents and siblings of schizophrenia patients for getting MS [158]. Brodziak and coworkers [159] formulate a theory that ERV causing MS and schizophrenia are activated during pregnancy by some infection of the mother.

2.2. MS and T1D

Several studies have analyzed the cooccurrence of MS and type 1 diabetes [91–96]. Most studies found higher incidence rates [96] or prevalence rates [91, 94] between both diseases than expected. Particularly adult women with type 1 diabetes have a dramatically higher risk of getting MS [95].

Both diseases have some features in common like the similar geographical distribution and increased family risk [160, 161]. Besides, susceptibility to both disorders is associated with common variants of the HLA-DRB1 and -DQB1 loci [162]. In contrast, an inverse risk-association between MS or T1D and distinct HLA alleles is discussed: HLA alleles known to confer to T1DM (DRB10401, DRB10404, DQB10302, DRB10301, and DQB10201) rarely occur in MS patients. HLA susceptibility genes for T1DM (DRB11501, DQB10602-DQA10102) predispose to MS [163]. Accordingly, our results are of special interest.

2.3. MS and ALS

The concurrence of MS and ALS was supposed to be extremely rare [100, 104, 105]. One reason might be that for a long time most detected cases were published as case reports [97–99, 101, 102]. In addition, large datasets were scanned for the simultaneous occurrence of MS and ALS [103, 108]. Taking all data together, it seems that the concurrence of MS and ALS is higher than expected [106, 107]. This association was also found for first-degree kinship [164, 165].

2.4. MS and HIV Infection

Considering the rare number of case reports [110, 114], the cooccurrence of MS and HIV infection seems to be an uncommon event. A first population-based register study [111] including 5,018 HIV patients and 50,149 controls failed to find an association (possibly due to the relatively small number of both groups) but showed a negative trend between both diseases. When increasing the number of both groups to 21,207 HIV positive patients and 5,298,496 controls significant negative association between both diseases was observed [113].

Some of the case reports analyzed patients who were treated with antiretroviral therapy. In the consequence, all of them showed less MS related deficits for over years [109, 112, 115]. Therefore, it seems imaginable that the treatment of HIV infection is coincidentally also treating or preventing the progression of MS [111, 113].

2.5. Schizophrenia and T1D

There are only few studies considering the cooccurrence of schizophrenia and type 1 diabetes (Table 1) on which 2 studies failed to find an association [85, 117] and 2 studies found a negative association between both diseases [116, 118].

In contrast, there is a higher prevalence of T1D in first-degree relatives of schizophrenia patients [85, 166, 167].

2.6. Schizophrenia and ALS

There are several case reports about the simultaneous occurrence of schizophrenia and ALS [119–126]. Most of them are historically old and the diagnosis is sometimes potentially questionable [168]. We failed to find any register-based study about patients with both diseases. At least there is one study showing the elevated risk for ALS in relatives of schizophrenic patients [169]. As patients with schizophrenia have a nearly threefold increase in overall mortality compared to controls [170], they might have a reduced chance of getting ALS because ALS usually occurs after the age of 50 [168].

2.7. Schizophrenia and HIV Infection

The cooccurrence of schizophrenia and HIV infection is described very often [127–132, 134, 136–138]. Susser and coworkers [133] reported a patient where HIV infection was determined before the onset of schizophrenia. Reasons for this coincidence were assumed to be mainly sexual activity accompanying high risk behavior [171, 172] and substance misuse with contaminated equipment and shared needles [173, 174]. Stewart and coworkers [131] observed that in Maryland, USA, 5.9% of patients with schizophrenia were HIV positive tested whereas the prevalence of HIV in the overall population in Maryland was about 0.032% [175]. Interestingly, there is also a higher risk for patients with HIV of getting schizophrenia and this elevated risk decreased after antiretroviral therapy [139].

2.8. Type 1 Diabetes and ALS

Unfortunately, several studies about diabetes and ALS do not distinguish between type 1 and type 2 diabetes [176, 177]. One problem is that the authors often do not have the possibility of distinguishing between both types [178] as some misclassification of hospital data is not avoidable. The very few studies of classified type 1 diabetes and ALS have shown inconsistent results [179]. Mariosa and coworkers [140] failed to detect more cases of type 1 diabetes in ALS patients compared to healthy controls whereas Turner and coworkers [107] showed an accumulation of insulin-dependent diabetes in ALS patients. Taking into account the age at ALS and diabetes diagnosis, there is an association between ALS and diabetes when patients are younger indicating that these diabetes cases are type 1 diabetes cases [140, 178]. All in all some authors speculate that type 1 diabetes increases the risk of getting ALS, while type 2 diabetes shows some protective effects [180].

2.9. Type 1 Diabetes and HIV Infection

There are lots of case reports about patients with type 1 diabetes as well as HIV infection [141–148, 150, 152]. This is not surprising as both diseases appear quite often in the world [50, 72].

In spite of the relatively frequent occurrence of both diseases there are no analyses about the kind of association between them. The only two register-based studies [149, 151] did not check for that.

2.10. ALS and HIV Infection

Unfortunately the classification between clinically definite ALS and ALS-like syndromes or disorders is often not very clear in the literature about patients with HIV so that most cases were clinically probable or possible cases of ALS [157]. Only 6 clinically definite ALS cases in patients with HIV infection have been found [153–157].

Interestingly, ALS [154, 155] and ALS-like disorders [181] in patients with HIV infection seem to respond very well to antiretroviral therapy and symptoms can disappear completely.

3. Conclusions

Some ERV-associated diseases seem to appear together more often than expected: MS and ALS, MS and T1D, MS and schizophrenia, schizophrenia and HIV infection, or ALS and T1D. On the other hand, some ERV-associated diseases seem to appear together less frequently than expected: MS and HIV infection or schizophrenia and T1D. Besides, amelioration of MS, ALS, and schizophrenia under antiretroviral therapy in HIV infected patients has been observed. Up to now there are mainly case reports for such effects available. One study compared HERV-K titers in HIV infected patients receiving successful highly active antiretroviral therapy (HAART) versus unsuccessful HAART. In this study, titers were undetectable in the first group and persistently higher in the other group [182]. All in all there is insufficient data about the cooccurrence of ERV-associated diseases and their response to antiretroviral therapy. In our opinion it would be reasonable to check HIV patients with cooccurring diseases regarding amelioration of these diseases under antiretroviral therapy in large register studies. If the positive results could be confirmed, then alternative therapy for putative ERV-associated diseases seems to be possible.

Competing Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

D. J. Griffiths, “Endogenous retroviruses in the human genome sequence,” Genome Biology, vol. 2, no. 6, pp. 1017.1–1017.5, 2001.

B. McClintock, “Controlling elements and the gene,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 21, pp. 197–216, 1956.

S. Ono, “So much ‘junk’ DNA in our genome,” Brookhaven Symposia in Biology, vol. 23, pp. 366–370, 1972.

I. A. Warren, M. Naville, D. Chalopin et al., “Evolutionary impact of transposable elements on genomic diversity and lineage-specific innovation in vertebrates,” Chromosome Research, vol. 23, no. 3, pp. 505–531, 2015.

H. E. Volkman and D. B. Stetson, “The enemy within: endogenous retroelements and autoimmune disease,” Nature Immunology, vol. 15, no. 5, pp. 415–422, 2014.

A. Hayward and A. Katzourakis, “Endogenous retroviruses,” Current Biology, vol. 25, no. 15, pp. R644–R646, 2015.

P. Jern and J. M. Coffin, “Effects of retroviruses on host genome function,” Annual Review of Genetics, vol. 42, pp. 709–732, 2008.

M. Sha, X. Lee, X.-P. Li et al., “Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis,” Nature, vol. 403, no. 6771, pp. 785–789, 2000.

A. Dupressoir, C. Lavialle, and T. Heidmann, “From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation,” Placenta, vol. 33, no. 9, pp. 663–671, 2012.

M. Oja, J. Peltonen, J. Blomberg, and S. Kaski, “Methods for estimating human endogenous retrovirus activities from EST databases,” BMC Bioinformatics, vol. 8, supplement 1, article no. S11, 2007.

C. Nellåker, Y. Yao, L. Jones-Brando, F. Mallet, R. H. Yolken, and H. Karlsson, “Transactivation of elements in the human endogenous retrovirus W family by viral infection,” Retrovirology, vol. 3, article 44, 2006.

N. Sutkowski, B. Conrad, D. A. Thorley-Lawson, and B. T. Huber, “Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen,” Immunity, vol. 15, no. 4, pp. 579–589, 2001.

N. Bhardwaj, F. Maldarelli, J. Mellors, and J. M. Coffin, “HIV-1 infection leads to increased transcription of human endogenous retrovirus HERV-K (HML-2) proviruses in vivo but not to increased virion production,” Journal of Virology, vol. 88, no. 19, pp. 11108–11120, 2014.

S. Kewitz and M. S. Staege, “Expression and regulation of the endogenous retrovirus 3 in Hodgkin's lymphoma cells,” Frontiers in Oncology, vol. 3, Article ID 00179, 2013.

M. Varela, T. E. Spencer, M. Palmarini, and F. Arnaud, “Friendly viruses: the special relationship between endogenous retroviruses and their host,” Annals of the New York Academy of Sciences, vol. 1178, pp. 157–172, 2009.

A. Dolei, “Endogenous retroviruses and human disease,” Expert Review of Clinical Immunology, vol. 2, no. 1, pp. 149–167, 2006.

E. Balada, J. Ordi-Ros, and M. Vilardell-Tarrés, “Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity,” Reviews in Medical Virology, vol. 19, no. 5, pp. 273–286, 2009.

H. Perron and A. Lang, “The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation,” Clinical Reviews in Allergy and Immunology, vol. 39, no. 1, pp. 51–61, 2010.

B. De la Hera, J. Varadé, M. García-Montojo et al., “Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: a meta-analysis,” PLoS ONE, vol. 9, no. 3, Article ID e90182, 2014.

H. Perron, N. Hamdani, R. Faucard et al., “Molecular characteristics of human endogenous retrovirus type-W in schizophrenia and bipolar disorder,” Translational Psychiatry, vol. 2, article e201, 2012.

M. J. Mason, C. Speake, V. H. Gersuk et al., “Low HERV-K(C4) copy number is associated with type 1 diabetes,” Diabetes, vol. 63, no. 5, pp. 1789–1795, 2014.

R. Douville, J. Liu, J. Rothstein, and A. Nath, “Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis,” Annals of Neurology, vol. 69, no. 1, pp. 141–151, 2011.

P. Browne, D. Chandraratna, C. Angood et al., “Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity,” Neurology, vol. 83, no. 11, pp. 1022–1024, 2014.

T. Vos, R. M. Barber, B. Bell et al., “Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease study 2013,” The Lancet, vol. 386, no. 9995, pp. 743–800, 2015.

T. Islam, W. J. Gauderman, W. Cozen, and T. M. Mack, “Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins,” Neurology, vol. 69, no. 4, pp. 381–388, 2007.

G. C. Ebers, A. D. Sadovnick, and N. J. Risch, “A genetic basis for familial aggregation in multiple sclerosis,” Nature, vol. 377, no. 6545, pp. 150–151, 1995.

A. D. Sadovnick and G. C. Ebers, “Epidemiology of multiple sclerosis: a critical overview,” Canadian Journal of Neurological Sciences, vol. 20, no. 1, pp. 17–29, 1993.

A. D. Sadovnick, P. A. Baird, R. H. Ward, J. M. Optiz, and J. F. Reynolds, “Multiple sclerosis. Updated risks for relatives,” American Journal of Medical Genetics, vol. 29, no. 3, pp. 533–541, 1988.

N. M. Nielsen, T. Westergaard, K. Rostgaard et al., “Familial risk of multiple sclerosis: a nationwide cohort study,” American Journal of Epidemiology, vol. 162, no. 8, pp. 774–778, 2005.

G. C. Ebers, D. E. Bulman, A. D. Sadovnick et al., “A population-based study of multiple sclerosis in twins,” New England Journal of Medicine, vol. 315, no. 26, pp. 1638–1642, 1986.

A. D. Sadovnick, H. Armstrong, G. P. A. Rice et al., “A population‐based study of multiple sclerosis in twins: update,” Annals of Neurology, vol. 33, no. 3, pp. 281–285, 1993.

A. Ascherio and K. L. Munger, “Environmental risk factors for multiple sclerosis. Part II: noninfectious factors,” Annals of Neurology, vol. 61, no. 6, pp. 504–513, 2007.

S. V. Ramagopalan, R. Dobson, U. C. Meier, and G. Giovannoni, “Multiple sclerosis: risk factors, prodromes, and potential causal pathways,” The Lancet Neurology, vol. 9, no. 7, pp. 727–739, 2010.

B. Hemmer, B. Kieseier, S. Cepok, and H.-P. Hartung, “New immunopathologic insights into multiple sclerosis,” Current Neurology and Neuroscience Reports, vol. 3, no. 3, pp. 246–255, 2003.

M. P. Pender and J. M. Greer, “Immunology of multiple sclerosis,” Current Allergy and Asthma Reports, vol. 7, no. 4, pp. 285–292, 2007.

A. Emmer, M. S. Staege, and M. E. Kornhuber, “The Retrovirus/Superantigen Hypothesis of Multiple Sclerosis,” Cellular and Molecular Neurobiology, vol. 34, no. 8, pp. 1087–1096, 2014.

H. Perron, J. A. Garson, F. Bedin et al., “Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 14, pp. 7583–7588, 1997.

A. Tselis, “Evidence for viral etiology of multiple sclerosis,” Seminars in Neurology, vol. 31, no. 3, pp. 307–316, 2011.

T. Christensen, “HERVs in neuropathogenesis,” Journal of Neuroimmune Pharmacology, vol. 5, no. 3, pp. 326–335, 2010.

J. M. Antony, G. Van Marle, W. Opii et al., “Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination,” Nature Neuroscience, vol. 7, no. 10, pp. 1088–1095, 2004.

S. R. Kay, A. Fiszbein, and L. A. Opler, “The positive and negative syndrome scale (PANSS) for schizophrenia,” Schizophrenia Bulletin, vol. 13, no. 2, pp. 261–276, 1987.

M. Tsuang, “Schizophrenia: genes and environment,” Biological Psychiatry, vol. 47, no. 3, pp. 210–220, 2000.

D. C. D'Souza, R. A. Sewell, and M. Ranganathan, “Cannabis and psychosis/schizophrenia: human studies,” European Archives of Psychiatry and Clinical Neuroscience, vol. 259, no. 7, pp. 413–431, 2009.

L. Krabbendam and J. Van Os, “Schizophrenia and urbanicity: a major environmental influence—conditional on genetic risk,” Schizophrenia Bulletin, vol. 31, no. 4, pp. 795–799, 2005.

R. H. Yolken, H. Karlsson, F. Yee, N. L. Johnston-Wilson, and E. F. Torrey, “Endogenous retroviruses and schizophrenia,” Brain Research Reviews, vol. 31, no. 2-3, pp. 193–199, 2000.

M. Leboyer, R. Tamouza, D. Charron, R. Faucard, and H. Perron, “Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene—environment interface,” World Journal of Biological Psychiatry, vol. 14, no. 2, pp. 80–90, 2013.

O. Frank, M. Giehl, C. Zheng, R. Hehlmann, C. Leib-Mösch, and W. Seifarth, “Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders,” Journal of Virology, vol. 79, no. 17, pp. 10890–10901, 2005.

D. Daneman, “Type 1 diabetes,” Lancet, vol. 367, no. 9513, pp. 847–858, 2006.

E. A. M. Gale, “Type 1 diabetes in the young: the harvest of sorrow goes on,” Diabetologia, vol. 48, no. 8, pp. 1435–1438, 2005.

W. You and M. Henneberg, “Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth,” BMJ Open Diabetes Research & Care, vol. 4, no. 1, 2016.

J. Östman, G. Lönnberg, H. J. Arnqvist et al., “Gender differences and temporal variation in the incidence of type 1 diabetes: results of 8012 cases in the nationwide Diabetes Incidence Study in Sweden 1983–2002,” Journal of Internal Medicine, vol. 263, no. 4, pp. 386–394, 2008.

H. Erlich, A. M. Valdes, J. Noble et al., “HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk analysis of the type 1 diabetes genetics consortium families,” Diabetes, vol. 57, no. 4, pp. 1084–1092, 2008.

B. M. Svoren, L. K. Volkening, J. R. Wood, and L. M. B. Laffel, “Significant vitamin D deficiency in youth with type 1 diabetes mellitus,” The Journal of Pediatrics, vol. 154, no. 1, pp. 132–134, 2009.

M. A. Atkinson, G. S. Eisenbarth, and A. W. Michels, “Type 1 diabetes,” The Lancet, vol. 383, no. 9911, pp. 69–82, 2014.

B. Conrad, R. N. Weissmahr, J. Böni, R. Arcari, J. Schüpbach, and B. Mach, “A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes,” Cell, vol. 90, no. 2, pp. 303–313, 1997.

V. J. Murphy, L. C. Harrison, W. A. Rudert et al., “Retroviral superantigens and type 1 diabetes mellitus,” Cell, vol. 95, no. 1, pp. 9–11, 1998.

Y. Kinjo, N. Matsuura, Y. Yokota et al., “Identification of nonsynonymous polymorphisms in the superantigen-coding region of IDDMK 1,222 and a pilot study on the association between IDDMK 1,222 and type 1 diabetes,” Journal of Human Genetics, vol. 46, no. 12, pp. 712–716, 2001.

S. Marguerat, W. Y. S. Wang, J. A. Todd, and B. Conrad, “Association of human endogenous retrovirus K-18 polymorphisms with type 1 diabetes,” Diabetes, vol. 53, no. 3, pp. 852–854, 2004.

G. Gambelunghe, I. Kockum, V. Bini et al., “Retrovirus-like long-terminal repeat DQ-LTR13 and genetic susceptibility to type 1 diabetes and autoimmune Addison's disease,” Diabetes, vol. 54, no. 3, pp. 900–905, 2005.

M. C. Kiernan, S. Vucic, B. C. Cheah et al., “Amyotrophic lateral sclerosis,” The Lancet, vol. 377, no. 9769, pp. 942–955, 2011.

S. Zoccolella, E. Beghi, G. Palagano et al., “Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: A Population Based Study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 1, pp. 33–37, 2008.

J. D. Mitchell and G. D. Borasio, “Amyotrophic lateral sclerosis,” The Lancet, vol. 369, no. 9578, pp. 2031–2041, 2007.

L. C. Wijesekera and P. N. Leigh, “Amyotrophic lateral sclerosis,” Orphanet Journal of Rare Diseases, vol. 4, no. 1, article no. 3, 2009.

A. Beleza-Meireles and A. Al-Chalabi, “Genetic studies of amyotrophic lateral sclerosis: controversies and perspectives,” Amyotrophic Lateral Sclerosis, vol. 10, no. 1, pp. 1–14, 2009.

F. Gros-Louis, C. Gaspar, and G. A. Rouleau, “Genetics of familial and sporadic amyotrophic lateral sclerosis,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1762, no. 11-12, pp. 956–972, 2006.

P. Pasinelli and R. H. Brown, “Molecular biology of amyotrophic lateral sclerosis: insights from genetics,” Nature Reviews Neuroscience, vol. 7, no. 9, pp. 710–723, 2006.

M. E. Westarp, P. Ferrante, H. Perron, P. Bartmann, and H. H. Kornhuber, “Sporadic ALS/MND: a global neurodegeneration with retroviral involvement?” Journal of the Neurological Sciences, vol. 129, pp. 145–147, 1995.

M. Manghera, J. Ferguson-Parry, and R. N. Douville, “TDP-43 regulates endogenous retrovirus-K viral protein accumulation,” Neurobiology of Disease, vol. 94, pp. 226–236, 2016.

W. Li, M. Lee, L. Henderson et al., “Human endogenous retrovirus-K contributes to motor neuron disease,” Science Translational Medicine, vol. 7, no. 307, p. 307ra153, 2015.

P. Hermans, J. Lundgren, B. Sommereijns et al., “Epidemiology of AIDS-related Kaposi's sarcoma in Europe over 10 years,” AIDS, vol. 10, no. 8, pp. 911–917, 1996.

E. L. Corbett, C. J. Watt, N. Walker et al., “The growing burden of tuberculosis: global trends and interactions with the HIV epidemic,” Archives of Internal Medicine, vol. 163, no. 9, pp. 1009–1021, 2003.

J. Fettig, M. Swaminathan, C. S. Murrill, and J. E. Kaplan, “Global epidemiology of HIV,” Infectious Disease Clinics of North America, vol. 28, no. 3, pp. 323–337, 2014.

I. H. Navarro, I. Alastrue, J. Del Amo et al., “Differences between women and men in serial HIV prevalence and incidence trends,” European Journal of Epidemiology, vol. 23, no. 6, pp. 435–440, 2008.

J. B. Alimonti, T. B. Ball, and K. R. Fowke, “Mechanisms of CD4⁺ T lymphocyte cell death in human immunodeficiency virus infection and AIDS,” Journal of General Virology, vol. 84, no. 7, pp. 1649–1661, 2003.

M. T. May and S. M. Ingle, “Life expectancy of HIV-positive adults: a review,” Sexual Health, vol. 8, no. 4, pp. 526–533, 2011.

M. Vincendeau, I. Göttesdorfer, J. M. Schreml et al., “Modulation of human endogenous retrovirus (HERV) transcription during persistent and de novo HIV-1 infection,” Retrovirology, vol. 12, article 27, pp. 1–17, 2015.

M. P. Laderoute, A. Giulivi, L. Larocque et al., “The replicative activity of human endogenous retrovirus K102 (HERV-K102) with HIV viremia,” AIDS, vol. 21, no. 18, pp. 2417–2424, 2007.

M. J. Gonzalez-Hernandez, J. D. Cavalcoli, M. A. Sartor et al., “Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 tat protein,” Journal of Virology, vol. 88, no. 16, pp. 8924–8935, 2014.

M. J. Gonzalez-Hernandez, M. D. Swanson, R. Contreras-Galindo et al., “Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1,” Journal of Virology, vol. 86, no. 15, pp. 7790–7804, 2012.

M. H. Hollender and P. P. Steckler, “Multiple sclerosis and schizophrenia: a case report,” Psychiatry in medicine, vol. 3, no. 3, pp. 251–257, 1972.

J. Kohler, H. Heilmeyer, and B. Volk, “Multiple sclerosis presenting as chronic atypical psychosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 51, no. 2, pp. 281–284, 1988.

A. Feinstein, G. Du Boulay, and M. A. Ron, “Psychotic illness in multiple sclerosis. A clinical and magnetic resonance imaging study,” British Journal of Psychiatry, vol. 161, no. 5, pp. 680–685, 1992.

P. J. H. Jongen, “Psychiatric onset of multiple sclerosis,” Journal of the Neurological Sciences, vol. 245, no. 1-2, pp. 59–62, 2006.

S. B. Patten, L. W. Svenson, and L. M. Metz, “Psychotic disorders in MS: population-based evidence of an association,” Neurology, vol. 65, no. 7, pp. 1123–1125, 2005.

W. W. Eaton, M. Byrne, H. Ewald et al., “Association of schizophrenia and autoimmune diseases: linkage of Danish national registers,” American Journal of Psychiatry, vol. 163, no. 3, pp. 521–528, 2006.

E. Sharma, N. P. Rao, G. Venkatasubramanian, R. V. Behere, S. Varambally, and B. N. Gangadhar, “Successful treatment of co-morbid schizophrenia and multiple sclerosis,” Asian Journal of Psychiatry, vol. 3, no. 4, pp. 235–236, 2010.

J.-H. Kang, Y.-H. Chen, and H.-C. Lin, “Comorbidities amongst patients with multiple sclerosis: A Population-based Controlled Study,” European Journal of Neurology, vol. 17, no. 9, pp. 1215–1219, 2010.

M. E. Benros, P. R. Nielsen, M. Nordentoft, W. W. Eaton, S. O. Dalton, and P. B. Mortensen, “Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study,” The American Journal of Psychiatry, vol. 168, no. 12, pp. 1303–1310, 2011.

R. A. Marrie, J. D. Fisk, B. N. Yu et al., “Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance,” BMC Neurology, vol. 13, article no. 16, 2013.

V. Johansson, C. Lundholm, J. Hillert et al., “Multiple sclerosis and psychiatric disorders: comorbidity and sibling risk in a nationwide Swedish cohort,” Multiple Sclerosis Journal, vol. 20, no. 14, pp. 1881–1891, 2014.

E. Wertman, N. Zilber, and O. Abramsky, “An association between multiple sclerosis and type I diabetes mellitus,” Journal of Neurology, vol. 239, no. 1, pp. 43–45, 1992.

K.-P. Wandinger, P. Trillenberg, H. Klüter, K. Wessel, and H. Kirchner, “Clinical and molecular findings in multiple sclerosis patients with type 1 diabetes mellitus,” Journal of Clinical Neuroscience, vol. 6, no. 5, pp. 373–374, 1999.

R. D. Henderson, C. J. Bain, and M. P. Pender, “The occurrence of autoimmune diseases in patients with multiple sclerosis and their families,” Journal of Clinical Neuroscience, vol. 7, no. 5, pp. 434–437, 2000.

M. G. Marrosu, E. Cocco, M. Lai, G. Spinicci, M. P. Pischedda, and P. Contu, “Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study,” The Lancet, vol. 359, no. 9316, pp. 1461–1465, 2002.

J. S. Dorman, A. R. Steenkiste, J. P. Burke, and M. Songini, “Type 1 diabetes and multiple sclerosis: together at last,” Diabetes Care, vol. 26, no. 11, pp. 3192–3193, 2003.

N. M. Nielsen, T. Westergaard, M. Frisch et al., “Type 1 diabetes and multiple sclerosis: a Danish population-based cohort study,” Archives of Neurology, vol. 63, no. 7, pp. 1001–1004, 2006.

W. J. Hader, B. Rozdilsky, and C. P. Nair, “The concurrence of multiple sclerosis and amyotrophic lateral sclerosis,” Canadian Journal of Neurological Sciences, vol. 13, no. 1, pp. 66–69, 1986.

C. Confavreux, T. Moreau, A. Jouvet, M. Tommasi, and G. Aimard, “Association sclérose latérale amyotrophique et sclérose en plaques,” Revue Neurologique, vol. 149, no. 5, pp. 351–353, 1993.

G. J. Dynes, C. J. Schwimer, S. M. Staugaitis, J. J. Doyle, A. P. Hays, and H. Mitsumoto, “Amyotrophic lateral sclerosis with multiple sclerosis: a clinical and pathological report,” Amyotrophic Lateral Sclerosis, vol. 1, no. 5, pp. 349–353, 2000.

B. Machner, S. Gottschalk, H. Kimmig, and C. Helmchen, “Kombiniertes Auftreten von amyotropher Lateralsklerose und Multipler Sklerose,” Der Nervenarzt, vol. 78, no. 12, pp. 1440–1443, 2007.

J. A. Allen, R. Stein, R. A. Baker, and H. Royden Jones, “Muscle atrophy associated with multiple sclerosis: a benign condition or the onset of amyotrophic lateral sclerosis?” Journal of Clinical Neuroscience, vol. 15, no. 6, pp. 706–708, 2008.

R. Vosoughi and M. S. Freedman, “Case report: multiple sclerosis and amyotrophic lateral sclerosis,” International Journal of MS Care, vol. 12, no. 3, pp. 142–145, 2010.

C. Hewitt, J. Kirby, J. R. Highley et al., “Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis,” Archives of Neurology, vol. 67, no. 4, pp. 455–461, 2010.

F. Trojsi, A. Sagnelli, G. Cirillo et al., “Amyotrophic lateral sclerosis and multiple sclerosis overlap: a case report,” Case Reports in Medicine, vol. 2012, Article ID 324685, 4 pages, 2012.

G. Li, M. M. Esiri, O. Ansorge, and G. C. DeLuca, “Concurrent multiple sclerosis and amyotrophic lateral sclerosis: where inflammation and neurodegeneration meet?” Journal of Neuroinflammation, vol. 9, no. 20, 2012.

A. Ismail, J. Cooper-Knock, J. R. Highley et al., “Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 84, no. 1, pp. 79–87, 2013.

M. R. Turner, R. Goldacre, S. Ramagopalan, K. Talbot, and M. J. Goldacre, “Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study,” Neurology, vol. 81, no. 14, pp. 1222–1225, 2013.

M. Seelen, P. T. C. van Doormaal, A. E. Visser et al., “Prior medical conditions and the risk of amyotrophic lateral sclerosis,” Journal of Neurology, vol. 261, no. 10, pp. 1949–1956, 2014.

H. Maruszak, B. J. Brew, G. Giovannoni, and J. Gold, “Could antiretroviral drugs be effective in multiple sclerosis? A case report,” European Journal of Neurology, vol. 18, no. 9, pp. e110–e111, 2011.

A. González-Duarte, C. Ramirez, R. Pinales, and J. Sierra-Madero, “Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection,” Journal of NeuroVirology, vol. 17, no. 5, pp. 504–508, 2011.

B. A. Nexø, L. Pedersen, H. T. Sørensen, and N. Koch-Henriksen, “Treatment of HIV and risk of multiple sclerosis,” Epidemiology, vol. 24, no. 2, pp. 331–332, 2013.

J. Chalkley and J. R. Berger, “Multiple sclerosis remission following antiretroviral therapy in an HIV-infected man,” Journal of NeuroVirology, vol. 20, no. 6, pp. 640–643, 2014.

J. Gold, R. Goldacre, H. Maruszak, G. Giovannoni, D. Yeates, and M. Goldacre, “HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 86, no. 1, pp. 9–12, 2015.

J. H. Chin, “Multiple sclerosis and HIV-1 infection: case report of a HIV controller,” Journal of NeuroVirology, vol. 21, no. 4, pp. 464–467, 2015.

F. Maulucci, M. Schluep, and C. Granziera, “Sustained disease-activity-free status in a woman with relapsing-remitting multiple sclerosis treated with antiretroviral therapy for Human Immunodeficiency Virus type 1 infection,” Journal of Multiple Sclerosis (Foster City), vol. 2, no. 4, pp. 2–4, 2015.

G. H. Finney, “Juvenile onset diabetes and schizophrenia?” The Lancet, vol. 334, no. 8673, pp. 1214–1215, 1989.

A. Reunanen, T. Kangas, J. Martikainen, and T. Klaukka, “Nationwide survey of comorbidity, use, and costs of all medications in finnish diabetic individuals,” Diabetes Care, vol. 23, no. 9, pp. 1265–1271, 2000.

H. Juvonen, A. Reunanen, J. Haukka et al., “Incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes mellitus,” Archives of General Psychiatry, vol. 64, no. 8, pp. 894–899, 2007.

A. Westphal, “Schizophrene Krankheitsprozesse und amyotrophische Lateralsklerose,” Archiv für Psychiatrie und Nervenkrankheiten, vol. 74, no. 1, pp. 310–325, 1925.

S. Androp, “Amyotrophic lateral sclerosis with psychosis,” The Psychiatric Quarterly, vol. 14, no. 4, pp. 818–825, 1940.

C. Meller, “Amyotrophic lateral sclerosis with psychosis (paranoid type),” Minnesota Medicine, vol. 23, no. 12, pp. 858–859, 1940.

W. K. Riley and J. G. Tirico, “Amyotrophic lateral sclerosis occurring in dementia praecox,” The Medical Bulletin of the Veterans' Administration, vol. 17, no. 2, pp. 180–181, 1940.

J. W. Friedlander and B. H. Kesert, “The role of psychosis in amyotrophic lateral sclerosis,” Journal of Nervous and Mental Disease, vol. 107, no. 3, pp. 243–250, 1948.

Y. Yase, N. Matsumoto, K. Azuma, Y. Nakai, and H. Shiraki, “Amyotrophic lateral sclerosis: association with schizophrenic symptoms and showing Alzheimer's tangles,” Archives of Neurology, vol. 27, no. 2, pp. 118–128, 1972.

R. H. Howland, “Schizophrenia and amyotrophic lateral sclerosis,” Comprehensive Psychiatry, vol. 31, no. 4, pp. 327–336, 1990.

J. F. Vázquez-Costa, E. Beltrán, P. Sopena et al., “Clinical and neuroimaging characterization of two C9orf72-positive siblings with amyotrophic lateral sclerosis and schizophrenia,” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 17, no. 3-4, pp. 297–300, 2016.

J. Volavka, A. Convit, P. Czobor, R. Douyon, J. O'Donnell, and F. Ventura, “HIV seroprevalence and risk behaviors in psychiatric inpatients,” Psychiatry Research, vol. 39, no. 2, pp. 109–114, 1991.

M. Sacks, H. Dermatis, S. Looser-Ott, and S. Perry, “Seroprevalence of HIV and risk factors for AIDS in psychiatric inpatients,” Hospital and Community Psychiatry, vol. 43, no. 7, pp. 736–737, 1992.

E. Susser, E. Valencia, and S. Conover, “Prevalence of HIV infection among psychiatric patients in a New York City men's shelter,” American Journal of Public Health, vol. 83, no. 4, pp. 568–570, 1993.

C. Silberstein, M. Galanter, M. Marmor, H. Lifshutz, K. Krasinski, and H. Franco, “HIV-1 among inner city dually diagnosed inpatients,” American Journal of Drug and Alcohol Abuse, vol. 20, no. 1, pp. 101–113, 1994.

D. L. Stewart, C. J. Zuckerman, and J. M. Ingle, “HIV seroprevalence in a chronically mentally ill population,” Journal of the National Medical Association, vol. 86, no. 7, pp. 519–523, 1994.

M. C. Mauri, L. Fabiano, S. Bravin, C. Ricci, and G. Invernizzi, “Schizophrenic patients before and after HIV infection: a case-control study,” Encephale, vol. 23, no. 6, pp. 437–441, 1997.

E. Susser, P. Colson, L. Jandorf et al., “HIV infection among young adults with psychotic disorders,” The American Journal of Psychiatry, vol. 154, no. 6, pp. 864–866, 1997.

J. Walkup, S. Crystal, and U. Sambamoorthi, “Schizophrenia and major affective disorder among Medicaid recipients with HIV/AIDS in New Jersey,” American Journal of Public Health, vol. 89, no. 7, pp. 1101–1103, 1999.

S. Leclerc, O. Brunschwig, Z. Berki-Benhaddad et al., “Patients schizophrènes infectés par le VIH traités par antirétroviraux: Prise en charge multidisciplinaire coordonnée (7 cas),” La Presse Médicale, vol. 34, no. 6, pp. 431–437, 2005.

R. Omoregie, M. O. Efam, J. C. Ihongbe, H. O. Ogefere, and E. U. Omokaro, “Seroprevalence of HIV infection among psychiatric patients in Benin City, Nigeria,” Neurosciences, vol. 14, no. 1, pp. 100–101, 2009.

S. Sanz-Cortés, E. Fashho-Rodriguez, T. Sánchez-Araña Moreno, S. Ruiz-Doblado, and J. Marín-Martín, “A case report of schizophrenia and HIV: HAART in association with clozapine,” Journal of Psychiatric Intensive Care, vol. 5, no. 1, pp. 47–49, 2009.

D. A. Polyanskiy, V. V. Kalinin, A. Y. Olshanskiy, A. V. Naryschkin, and E. Y. Kholodov, “Prediction of the changes of immunological status and psychopathological data in HIV-infected schizophrenia patients,” Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova, vol. 2015, no. 5, pp. 76–81, 2015.

M. Helleberg, M. G. Pedersen, C. B. Pedersen, P. B. Mortensen, and N. Obel, “Associations between HIV and schizophrenia and their effect on HIV treatment outcomes: a nationwide population-based cohort study in Denmark,” The Lancet HIV, vol. 2, no. 8, pp. e344–e350, 2015.

D. Mariosa, F. Kamel, R. Bellocco, W. Ye, and F. Fang, “Association between diabetes and amyotrophic lateral sclerosis in Sweden,” European Journal of Neurology, vol. 22, no. 11, pp. 1436–1442, 2015.

J. Vendrell, I. Conget, A. Muñoz, J. Vidal, and A. Nubiola, “Diabetes in aids patients,” The Lancet, vol. 332, no. 8621, p. 1196, 1988.

J. P. A. Ioannidis, V. R. Iacoviello, and M. H. Samore, “Insulin-dependent diabetes in AIDS,” AIDS, vol. 8, no. 4, pp. 556–557, 1994.

D. Vittecoq, D. Zucman, I. Auperin, and J. Passeron, “Transient insulin-dependent diabetes mellitus in an HIV-infected patient receiving didanosine,” AIDS, vol. 8, no. 9, p. 1351, 1994.

C. Chidiac, S. Alfamdari, J. Caron, and Y. Mouton, “Diabetes mellitus following treatment of AIDS with didanosine,” AIDS, vol. 9, no. 2, pp. 215–216, 1995.

I. Abdel-Khalek, H. J. Moallem, S. Fikrig, and S. Castells, “New onset diabetes mellitus in an HIV-positive adolescent,” AIDS Patient Care and STDs, vol. 12, no. 3, pp. 167–169, 1998.

E. M. Evans, F. Nye, N. J. Beeching, and G. V. Gill, “'Disappearing diabetes'—resolution of apparent Type 1 diabetes in a patient with AIDS and cytomegalovirus (CMV) infection,” Diabetic Medicine, vol. 22, no. 2, pp. 218–220, 2005.

C. A. Sheffield, M. P. Kane, and R. S. Busch, “Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection,” Pharmacotherapy, vol. 27, no. 10, pp. 1449–1455, 2007.

R. Bargman, A. Freedman, M. Vogiatzi, and R. Motaghedi, “Autoimmune type 1 diabetes mellitus in a perinatally HIV infected patient with a well-preserved immune system,” Journal of Pediatric Endocrinology and Metabolism, vol. 22, no. 4, pp. 369–372, 2009.

C. I. A. Kabati, H. B. Maurice, T. Mselle, and M. Urio, “Evaluation of the prevalence of insulin dependent diabetes mellitus in HIV/AIDS patients in Muhimbili National Hospital, Dar es Salaam, Tanzania,” Tanzania Journal of Natural and Applied Sciences, vol. 1, no. 2, pp. 164–173, 2012.

D. Takarabe, Y. Rokukawa, Y. Takahashi et al., “Autoimmune diabetes in HIV-infected patients on highly active antiretroviral therapy,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 8, pp. 4056–4060, 2010.

L. D. Rasmussen, E. R. Mathiesen, G. Kronborg, C. Pedersen, J. Gerstoft, and N. Obel, “Risk of diabetes mellitus in persons with and without HIV: a Danish Nationwide Population-Based Cohort Study,” PLOS ONE, vol. 7, no. 9, Article ID e44575, 2012.

S. Kamei, H. Kaneto, M. Hashiramoto et al., “Case of newly onset type 1 diabetes after highly active antiretroviral therapy against HIV infection,” Journal of Diabetes Investigation, vol. 6, no. 3, pp. 367–368, 2015.

P. M. Hoffman, B. W. Festoff, L. T. Giron Jr., L. C. Hollenbeck, R. M. Garruto, and F. W. Ruscetti, “Isolation of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis,” New England Journal of Medicine, vol. 313, no. 5, pp. 324–325, 1985.

D. J. L. MacGowan, S. N. Scelsa, and M. Waldron, “An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy,” Neurology, vol. 57, no. 6, pp. 1094–1097, 2001.

A. Moulignier, A. Moulonguet, G. Pialoux, and W. Rozenbaum, “Reversible ALS-like disorder in HIV infection,” Neurology, vol. 57, no. 6, pp. 995–1001, 2001.

S. Zoccolella, S. Carbonara, D. Minerva et al., “A case of concomitant amyotrophic lateral sclerosis and HIV infection,” European Journal of Neurology, vol. 9, no. 2, pp. 180–182, 2002.

A. Verma and J. R. Berger, “ALS syndrome in patients with HIV-1 infection,” Journal of the Neurological Sciences, vol. 240, no. 1-2, pp. 59–64, 2006.

W. W. Eaton, M. G. Pedersen, P. R. Nielsen, and P. B. Mortensen, “Autoimmune diseases, bipolar disorder, and non-affective psychosis,” Bipolar Disorders, vol. 12, no. 6, pp. 638–646, 2010.

A. Brodziak, E. Ziółko, and M. Muc-Wierzgoń, “Activation of endogenous retroviruses by infection of the mother's body during early pregnancy—the likely cause of schizophrenia and multiple sclerosis,” Clinical and Experimental Medical Letters, vol. 52, no. 1-2, pp. 1–6, 2011.

A. E. Handel, L. Handunnetthi, G. C. Ebers, and S. V. Ramaǵopalan, “Type 1 diabetes mellitus and multiple sclerosis: common etiological features,” Nature Reviews Endocrinology, vol. 5, no. 12, pp. 655–664, 2009.

P. Tettey, S. Simpson, B. V. Taylor, and I. A. F. Van Der Mei, “The co-occurrence of multiple sclerosis and type 1 diabetes: shared aetiologic features and clinical implication for MS aetiology,” Journal of the Neurological Sciences, vol. 348, no. 1-2, pp. 126–131, 2015.

M. G. Marrosu, C. Motzo, R. Murru et al., “The co-inheritance of type 1 diabetes and multiple sclerosis in Sardinia cannot be explained by genotype variation in the HLA region alone,” Human Molecular Genetics, vol. 13, no. 23, pp. 2919–2924, 2004.

B. M. Lobnig, E. Chantelau, G. Vidgrén, A. A. L. Van Landeghem, L. Kinnunen, and E. Tuomilehto-Wolf, “HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases,” Diabetes and Metabolism, vol. 28, no. 3, pp. 217–221, 2002.

K. Hemminki, X. Li, J. Sundquist, and K. Sundquist, “Familial risks for amyotrophic lateral sclerosis and autoimmune diseases,” Neurogenetics, vol. 10, no. 2, pp. 111–116, 2009.

M. Etemadifar, S.-H. Abtahi, M. Akbari, and A.-H. Maghzi, “Multiple sclerosis and amyotrophic lateral sclerosis: is there a link?” Multiple Sclerosis Journal, vol. 18, no. 6, pp. 902–904, 2012.

C. M. Gilvarry, P. C. Sham, P. B. Jones et al., “Family history of autoimmune diseases in psychosis,” Schizophrenia Research, vol. 19, no. 1, pp. 33–40, 1996.

P. Wright, P. C. Sham, C. M. Gilvarry et al., “Autoimmune diseases in the pedigrees of schizophrenic and control subjects,” Schizophrenia Research, vol. 20, no. 3, pp. 261–267, 1996.

E. W. Stommel, D. Graber, J. Montanye, J. A. Cohen, and B. T. Harris, “Does treating schizophrenia reduce the chances of developing amyotrophic lateral sclerosis?” Medical Hypotheses, vol. 69, no. 5, pp. 1021–1028, 2007.

A. B. Goodman, “Elevated risks for amyotrophic lateral sclerosis and blood disorders in Ashkenazi schizophrenic pedigrees suggest new candidate genes in schizophrenia,” American Journal of Medical Genetics, vol. 54, no. 3, pp. 271–278, 1994.

D. W. Black, “Iowa record-linkage study: death rates in psychiatric patients,” Journal of Affective Disorders, vol. 50, no. 2-3, pp. 277–282, 1998.

F. Cournos, J. R. Guido, S. Coomaraswamy, H. Meyer-Bahlburg, R. Sugden, and E. Horwath, “Sexual activity and risk of HIV infection among patients with schizophrenia,” American Journal of Psychiatry, vol. 151, no. 2, pp. 228–232, 1994.

L. Grassi, M. Pavanati, R. Cardelli, S. Ferri, and L. Peron, “HIV-risk behaviour and knowledge about HIV/AIDS among patients with schizophrenia,” Psychological Medicine, vol. 29, no. 1, pp. 171–179, 1999.

S. Wright, K. Gournay, E. Glorney, and G. Thornicroft, “Dual diagnosis in the suburbs: prevalence, need, and in-patient service use,” Social Psychiatry and Psychiatric Epidemiology, vol. 35, no. 7, pp. 297–304, 2000.

R. Gray, E. Brewin, J. Noak, J. Wyke-Joseph, and B. Sonik, “A review of the literature on HIV infection and schizophrenia: implications for research, policy and clinical practice,” Journal of Psychiatric and Mental Health Nursing, vol. 9, no. 4, pp. 405–409, 2002.

E. Kassira, A. Swetz, R. Bauserman, N. Tomoyasu, E. Caldeira, and L. Solomon, “HIV and AIDS surveillance among inmates in Maryland prisons,” Journal of Urban Health, vol. 78, no. 2, pp. 256–263, 2001.

H. Hamasaki, Y. Takeuchi, Y. Masui et al., “Development of diabetes in a familial amyotrophic lateral sclerosis patient carrying the I113T SOD1 mutation,” Neuroendocrinology Letters, vol. 36, no. 5, pp. 414–416, 2015.

Y. Sun, C.-J. Lu, R.-C. Chen, W.-H. Hou, and C.-Y. Li, “Risk of amyotrophic lateral sclerosis in patients with diabetes: A Nationwide Population-Based Cohort Study,” Journal of Epidemiology, vol. 25, no. 6, pp. 445–451, 2015.

M.-A. Kioumourtzoglou, R. S. Rotem, R. M. Seals, O. Gredal, J. Hansen, and M. G. Weisskopf, “Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study,” JAMA Neurology, vol. 72, no. 8, pp. 905–911, 2015.

A. Lekoubou, T. E. Matsha, E. Sobngwi, and A. P. Kengne, “Effects of diabetes mellitus on amyotrophic lateral sclerosis: a systematic review,” BMC Research Notes, vol. 7, article 171, 2014.

A. Jawaid, J. A. Brown, and P. E. Schulz, “Diabetes mellitus in amyotrophic lateral sclerosis: Dr Jekyll or Mr Hyde?” European Journal of Neurology, vol. 22, no. 11, pp. 1419–1420, 2015.

L. A. Cone, R. Nazemi, and M. O. Cone, “Reversible ALS-like disorder in HIV infection. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy,” Neurology, vol. 59, no. 3, pp. 474–475, 2002.

R. Contreras-Galindo, S. Almodóvar-Camacho, S. González-Ramırez, E. Lorenzo, and Y. Yamamura, “Comparative longitudinal study of HERV-K and HIV-1 RNA titers in HIV-1 infected patients receiving successful versus unsuccessful highly active antiretroviral therapy,” AIDS Research and Human Retroviruses, vol. 23, no. 9, pp. 1083–1086, 2007.