HSV-1 and Endogenous Retroviruses as Risk Factors in Demyelination

Abstract

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS.

Keywords: demyelination; endogenous retroviruses; herpes simplex virus type 1; herpesviruses; multiple sclerosis; transposable elements.

Figure 1

Transposable Elements (TEs). TEs can be organized into two major categories: retrotransposons (retroelements or class I elements) and DNA transposons (class II elements). Both types of TEs can be either autonomous or non-autonomous. Autonomous TEs encode reverse transcriptase (RT) and other proteins required for replication and transposition, whereas non-autonomous elements do not encode these proteins and need other TEs for their mobilization. Retrotransposons can be divided into two groups, according to the presence or absence of long terminal repeats (LTRs) flanking internal coding regions. The canonical autonomous LTR retrotransposons contain a small number of open reading frames (ORFs). Most elements contain an ORF including gag and pol domains, and endogenous retroviruses (ERVs) contain an ORF for env. Gag encodes a structural polyprotein, and pol encodes enzymatic activities: protease, RT, integrase, and ribonuclease H. ERVs contain a primer-binding site (PBS) located between the 5′LTR and gag, and a polypurine trait (PPT) located between env and the 3′LTR. The PBS binds the cellular tRNA priming the synthesis of the (–)strand DNA, and the PPT acts as a primer for the (+)strand DNA. Non-LTR retrotransposons include long interspersed nuclear elements (LINEs), and short interspersed nuclear elements (SINEs). The canonical LINE-1 element has two ORFs (ORF1 and ORF2) flanked by 5′ and 3′ UTRs; the 5′ UTR includes an RNA polymerase II promoter, and the element ends with a poly (A) tail. The canonical Alu element consists of two monomers (A and B) separated by an (A)-rich linker region, and ends with a poly (A) tail. A and B boxes are transcriptional promoters for RNA polymerase III. In DNA transposons, the transposase is flanked by terminal inverted repeats (TIRs).

Figure 2

Mechanisms for mobilization. (A) DNA transposons move via a “cut and paste” mechanism, by which a transposase (T) mediates double-strand DNA cleavage and insertion. The DNA sequence is excised by the transposase from one region (donor DNA) and integrated into another region of the genome (target DNA). Transposases are flanked by terminal inverted repeats (TIRs). (B) Retrotransposons move via a “copy and paste” mechanism, using RT to transcribe the RNA back into DNA and integrases or endonucleases to insert it into a new location. After insertions, the DNA at the target site duplicates, producing target site duplications (TSDs).

Figure 3

Retrovirus endogenization and exaptation. During replication, retroviral RNA is reverse-transcribed, giving rise to a double-stranded cDNA provirus that will be then integrated into the cellular genome of somatic cells. However, when the exogenous retroviruses infected germline cells, the integrated retroviruses began to be inherited in a Mendelian fashion. Endogenized retroviruses were vertically transmitted and fixed into the human genome. Over the course of evolution, endogenous retroviruses accumulated mutations (white boxes) and underwent gene capture and exaptation, by which retroviral genes started to perform new physiological functions. For example, syncytins are env genes of retroviral origin captured by mammals.

Figure 4

Classification of human endogenous retroviruses (HERVs). HERVs can be classified into three groups: class I (genus Gammaretrovirus), class II (genus Betaretrovirus), and class III (genus Spumavirus-related). Genus Gammaretrovirus includes families HERV-F, H, I, E, R, P, T, W as well as ERV-FTD and FRD. Genus Betaretrovirus includes the HERV-K family (HML1-10 subfamilies). Genus Spumavirus-related family includes the HERV-L family.

Figure 5

Physiological and pathological functions of syncytin. (A) When the embryo reaches the blastocyst stage, it undergoes implantation into the endometrium of the uterine wall. During implantation, the trophoblast (cells that form the outer layer of the blastocyst) develops into two layers: the cytotrophoblast and syncytiotrophoblast. The syncytiotrophoblast invades the maternal endometrium and directly contacts the maternal capillaries. Syncytin-1 plays a major role in syncytiotrophoblast cell fusion and, therefore, in embryonic development. (B). Besides cell-to-cell fusion, syncytin-1 exerts an immunosuppressive function that inhibits rejection of the fetus by the maternal immune system. However, syncytin-1 exerts also pathological functions, such as neuroinflammation and tumor-endothelial cell fusion. (OLs = oligodendrocytes).

Figure 6

Role of HSV-1 in HERVs activation and immune response. The figure summarizes relevant effects of HSV-1 on HERVs transcription and the synergistic effects of both viruses on immune response.