Evolutionary Medicine of Retroviruses in the Human Genome

Abstract

Humans are infected with many viruses, and the immune system mostly removes viruses and the infected cells. However, certain viruses have entered the human genome. Of the human genome, ∼45% is composed of transposable elements (long interspersed nuclear elements [LINEs], short interspersed nuclear elements [SINEs] and transposons) and 5-8% is derived from viral sequences with similarity to infectious retroviruses. If integration of retrovirus occurs in a germline, the integrated viral sequences are heritable. Accumulation of viral sequences has created the current human genome. This article summarizes recent studies of retroviruses in humans and bridges clinical fields and evolutionary genetics. First, we report the repertories of human-infective retroviruses. Second, we review endogenous retroviruses in the human genome and diseases associated with endogenous retroviruses. Third, we discuss the biological functions of endogenous retroviruses and propose the concept of accelerated human evolution via viruses. Finally, we present perspectives of virology in the field of evolutionary medicine.

INTRODUCTION

Currently there are 5,630 confirmed virus species on the earth,¹ and Anthony et al estimated that at least 320,000 undiscovered viruses infect mammalian hosts.² RNA viruses are a major threat to human health, and severe acute respiratory syndrome (SARS) coronavirus, Ebola virus and Middle East respiratory syndrome (MERS) coronavirus are recently known to cause pandemics.³ Of the discovered virus species, 214 viruses are known human-infective RNA viruses and 9 viruses are retroviruses (Table 1 ).³ The human-infective retroviruses are human T-lymphotropic viruses (HTLV), human immunodeficiency viruses (HIV) and simian foamy viruses (SFV), and consist of 3 genuses (Deltaretrovirus, Lentivirus and Spumavirus, respectively; Table 1). The range of hosts of retroviruses is narrow, and HIV can be acquired only from humans although HTLV and SFV are from suspected zoonotic origin and intraspecies transmission to humans after first infection in nonhuman primates.^{3 , 4} Of the human genome, 5-8% are endogenous retroviruses derived from viral sequences with similarity to the infectious retroviruses. Understanding the endogenous retroviruses is clinically important because the accumulation of viral sequences has created the current human genome, and it can cause diseases associated with endogenous retroviruses.

TABLE 1.

Human-infective retroviruses (Retroviridae species).

Species	Genus	References
PTLV-1	Deltaretrovirus	45
PTLV-2	Deltaretrovirus	46
PTLV-3	Deltaretrovirus	47
HIV-1	Lentivirus	48
HIV-2	Lentivirus	49
SIV	Lentivirus	50
SFVagm	Spumavirus	51
SFVmac	Spumavirus	52
SFV	Spumavirus	53

The table shows human-infective retroviruses: Primate T-lymphotropic virus (PTLV), human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), African green monkey simian foamy virus (SFVagm), macaque simian foamy virus (SFVmac) and simian foamy virus (SFV).

HUMAN-INFECTIVE RETROVIRUSES

Retroviruses consist of a dimer of single-stranded positive sense RNA enclosed in a capsid of a lipid bilayer envelope and contain a reverse transcriptase (RT) enzyme.⁵ The retrovirus genome is composed of 3 genes (gag, pol and env) enclosed between 2 long terminal repeats: pol (polymerase) has RT and integrase function, gag (group antigens) is a polyprotein with processed matrix and core proteins, and env encodes envelope proteins (Figure 1 A).⁵

FIGURE 1.

Structure of a retrovirus genome and HERV-K. A, The retrovirus genome has at least 3 genes (gag, pol and env) enclosed between 2 long terminal repeats. B, HERV-K env genes originate 2 proteins (np9 and rec) with a different length, and np9 proteins present 292bp deletion.

Primate T-lymphotropic viruses (PTLVs) are composed of 3 distinct groups (PTLV-1, -2 and -3) and are also called HTLVs in the case of infections in humans. PTLVs are known to cause adult T-cell lymphoma/leukemia, and inflammation due to T lymphocytes in several tissues presents as bronchitis, uveitis and demyelinating diseases called HTLV-1 associated myelopathy/tropical spastic paraparesis. PTLV-1 is the first retrovirus discovered from T-cell lymphoma, and PTLV-2 was found originally in a patient with hairy cell leukemia.^{6 , 7} Lately, PTLV-3 was discovered in Central Africa,⁸ and Wolfe et al suggested that hunting and eating bushmeat is one of the transmission routes of PTLV beyond species. PTLVs are transmittable via sexual and maternal contact.⁹

HIV destroys lymphoid CD4 T cells by pyroptosis with caspase-1 activation and causes acquired immunodeficiency syndrome.^{10 , 11} HIV-1 and -2 are classified into 4 groups (M-P) and 8 groups (A-H), respectively, and are further finely grouped into subtypes whose configuration changes frequently.¹² The origin of HIV-1 and -2 is believed to be independent transmission from different primates, since the HIV-1 and -2 sequences are similar to those of chimpanzee simian immunodeficiency virus (SIV) and Old World monkey SIV, respectively.¹³ HIVs are transmittable via direct contact by sexual, iatrogenic, broken skin and maternal routes, and SIV can be transmitted to humans from simian blood cells through broken skin.13, 14, 15

The association of SFV with specific diseases has not been clarified, although the prevalence of SFV in humans has been well studied.¹⁶ After infection by SFV, it has been observed that foamy degeneration and vacuolization occurs in the infected cells, with formation of numerous cytoplasmic vacuoles, and glycoproteins produced are expressed at the cell surface and result in fusion of cells.¹⁶ SFVs are known to be transmittable among simians only via direct contact with broken skin.17, 18, 19

ENDOGENOUS RETROVIRUSES IN HUMAN GENOME

The reverse transcripted retroviral genome can integrate into a host genome, and the integrated genome is heritable if the retrovirus infects a germ line of the host. The integrated retroviral sequence, which is 7-11 kb, is called a provirus.⁵ Of the human genome, 5-8% is believed to comprise proviruses with sequence similarity to genes and fragments of retroviruses, and the provirus sequences are also called human endogenous retroviruses (HERVs).²⁰ Some HERVs still have open reading frames with the possibility of protein expression. There have been 3,173 HERV sequences identified from the human genome, and 39 canonical types of HERVs are categorized as classes I, II and III on the basis of sequences similar to different genera of infectious retroviruses (Gammaretrovirus/Epsilonretrovirus, Betaretrovirus and Spumaretrovirus, respectively).^{5 ,} 21, 22

It is believed that HERVs are associated with physiological functions and certain diseases based on model animal studies, but the role of HERVs is still under debate.⁵ Multiple sclerosis (MS) is caused by the destruction of myelin and oligodendrocytes, leading to axonal disruption in the brain and spinal cord. In MS patients, it has been reported that expression or abnormal representation of HERV-H, -K and -W and a polymorphism in HERV-Fc1 occurs.²³ Secretion of env proteins coded by HERV-W in oligodendroglial precursor cells reduces oligodendroglial differentiation via activation of Toll-like receptor, and blocking their differentiation results in demyelinated and degenerating axons.²⁴ HERV env proteins are related to complex pathological disorders and can be one of the targets for therapeutic approach.²⁵ A monoclonal antibody against a HERV-W env protein is under clinical trial as a therapeutic approach for MS.^{26 , 27}

Upregulation of HERV-W was also reported in blood cells and peripheral nerve lesions of chronic inflammatory demyelinating polyradiculoneuropathy patients, and chronic inflammatory demyelinating polyradiculoneuropathy might be caused by Toll-like receptor-mediated effects of env proteins on primary Schwann cells.²⁸ In sporadic amyotrophic lateral sclerosis patients, env proteins of HERV-K are specifically expressed in cortical and spinal neurons and can cause cellular degeneration.²⁹ RT proteins encoded by the pol gene of HERV-K have been detected in brain and blood tissues, but transmission of amyotrophic lateral sclerosis has not yet been demonstrated.^{23 , 30}

HERVs are believed to be pathogenic in autoimmune rheumatic diseases and cancers, with evidence of increased expression of HERVs at the protein and RNA levels. Increased expression of HERVs was reported in patients with rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis and Sjogren's syndrome.³¹ Nakkuntod et al reported hypomethylation of HERV-E and -K in systemic lupus erythematosus patients, and a lower methylation level can allow higher expression of HERV genes.³² HERV activation has also been reported in breast cancer, lymphoma, melanoma, ovarian cancer and prostate cancer, and the expression of env proteins can be involved in tumorigenesis via inducing cell-cell fusion.³³ In addition, it is known that sequences derived from HERVs can be a trigger of cancers if partial sequences of HERVs or HERV itself translocates to regulatory regions of oncogenes.³³ Tomlins et al reported that a translocation of HERV-K upstream of ETS translocation variant 1 caused cancerogenesis via enhanced expression of ETS translocation variant 1.³⁴ HERV-K env genes originate 2 proteins (np9 and rec) with a different length by alternative splicing, and np9 proteins present 292bp deletion but rec is not (Figure 1B).²⁵ It has been reported that rec and np9 contribute to tumorigenesis.²⁵ Viral infections induced HERVs transactivation, and the HERVs transactivation causes enhancement of several signal transductions and transcription factors.³⁵ HERV-K transactivated by Kaposi's sarcoma-associated herpes virus is suggested the involvement of tumorigenesis in Kaposi's sarcoma.³⁶

EVOLUTIONARY MEDICINE OF ENDOGENOUS RETROVIRUSES

The endogenous retroviruses remaining in the genome should be neutral or advantageous. If all endogenous retroviruses were harmful, all of the retroviruses would have been excluded from the genome during evolution leading to humans. HERV-K is a case of beneficial endogenous retroviruses and has been integrated stepwise during primate evolution.³⁷ It is known that HIV-1 infection stimulates a T cell response to HERV-K antigens because of protein similarity.³⁸ Monde et al showed that gag proteins encoded by HERV-K changed the size and morphology of HIV particles, and these changes caused significant diminishing of the release efficiency and infectivity of HIV viruses.³⁹

Vargiu et al estimated that HERVs diverged in the host genome from 6 to 100 million years ago, and this means the integration of HERVs occurred from after the divergence of Eutheria to the divergence between chimpanzees and humans.²² Syncytin-1 and -2 belong to the HERV-W and -FRD families, respectively, and both of them express env proteins with fusogenic activity and are involved in fusion of trophoblast cells.⁴⁰ The syncytin-1 and -2 sequences are believed to have integrated 12-80 million years ago, and at the same time these sequences obtained mammalian-specific placental function.⁴¹ As in this case, HERVs acquired essential functions that can be evolutionarily preserved.

Retroviral sequences can accelerate the evolution of host genomes. In the host genome, the integrated retroviral elements can be a promotor or enhancer and provide alternative and aberrant sites for splicing of transcripts.⁵ Endogenous retroviruses can enhance recombination and rearrangement of the host genome via long terminal repeats, while crossover between HERV-I loci on the Y chromosome is a cause of male infertility due to deletion of an azoospermia factor-a region.⁴²

CONCLUSIONS

In this review, we focused on known human-infective retroviruses and endogenous retroviruses in the human genome. It was previously believed that only retroviruses can integrate into the host genome, but Horie et al showed that sequences derived from nonretroviral RNA exist in the human genome. Bornaviruses, negative sense single stranded RNA viruses, encode 6 genes (M, X, P, N, G and L), and 2 proteins with high similarity to N genes, called endogenous borna-like N -1 and -2, have been found.⁴³ It is believed that N genes of bornaviruses integrated by RT activation of long interspersed nuclear element, and this mechanism can enhance the integration of any viruses without dependence on retroviruses.⁴³ The mechanism is the same as a system of making a processed gene, which was the evolutionary force to increase a member of a gene family in the human evolution.⁴⁴ If the activation of long interspersed nuclear element enhances the integration of any viruses, there should be many more known and unknown viruses in the human genome. Whole genome sequencing of viruses and infected hosts will help to discover new viral sequences in the human genome, and the number of viral sequences in the genome could be higher than the current estimation based on the sequence similarity of only retroviruses (5-8%). Most viruses can infect specific tissues or cells in the human body, and it is not clear how a virus can recognize specific cells and invade cells. If there is affinity between the virus and cells, the virus might tend to get into the genome of specific cells with high affinity. If there is a niche in the localization of the virus, the niche might allow an entry route of the virus and thereby determine integration.

AUTHOR CONTRIBUTIONS

Y.K. and S.A. conceived and designed the analysis, and Y.K. wrote the paper.