Human Endogenous Retrovirus K (HML-2) in Health and Disease

Abstract

Human endogenous retroviruses (HERVs) are derived from exogenous retrovirus infections in the evolution of primates and account for about 8% of the human genome. They were considered as silent passengers within our genomes for a long time, however, reactivation of HERVs has been associated with tumors and autoimmune diseases, especially the HERV-K (HML-2) family, the most recent integration groups with the least number of mutations and the most biologically active to encode functional retroviral proteins and produce retrovirus-like particles. Increasing studies are committed to determining the potential role of HERV-K (HML-2) in pathogenicity. Although there is still no evidence for HERV-K (HML-2) as a direct cause of diseases, aberrant expression profiles of the HERV-K (HML-2) transcripts and their regulatory function to their proximal host-genes were identified in different diseases. In this review, we summarized the advances between HERV-K (HML-2) and diseases to provide basis for further studies on the causal relationship between HERV-K (HML-2) and diseases. We recommended more attention to polymorphic integrated HERV-K (HML-2) loci which could be genetic causative factors and be associated with inter-individual differences in tumorigenesis and autoimmune diseases.

Keywords: HERV-K (HML-2); LTR; diseases; polymorphic integration; viral proteins.

FIGURE 1

Diagram of the genome wide distribution of HERV-K (HML-2). There are 1098 HERV-K (HML-2) loci in human genome, including reference (hg19) and non-reference loci. Among them, there are 26 reported human-specific loci and 71 polymorphic integration loci, which have been highlighted with different symbols in the figure (except one polymorphic locus, solo-LTR946, located in GL000219.1). Detailed information of all the 1098 HERV-K (HML-2) loci were summarized in Xue et al. (2020).

FIGURE 2

Schematic diagram of potential pathogenetic mechanisms of HERV-K (HML-2). The polymorphic integrated HERV-K (HML-2) locus can have three different status in different individuals, including: (i) Pre-integration: without both viral protein coding sequences and LTRs; (ii) Provirus integration: possesses both viral protein coding sequences and LTRs; (iii) Solo-LTR integration: only possesses an LTR sequence. The presence or absence of viral proteins coding sequences or LTRs may reveal different pathogenetic mechanisms: (A–E) show viral proteins produced by HERV-K (HML-2) cause aberrant biological phenomenon; (F–I) show regulatory functions of LTRs. (A,B) Env protein induces cell-cell fusion and epithelial mesenchymal transition (EMT) which could contribute to tumorigenesis. (C,D) Accessory proteins, Rec and Np9, are suggested as oncogenic proteins causing c-myc depression and androgen receptor deregulation. (E) Viral proteins, such as Env and Np9, can regulate different signal pathways related to cell growth and proliferation. (F) LTRs can significantly affect their proximal host genes in addition to regulating viral gene expression because of the possession of regulatory elements. LTRs can act as alternative promoters, enhancers, splicing sites, and poly (A) signals. (G) LTR sequence variation, causing transcription factor binding site polymorphism, induce different promoter expression patterns. (H) The presence of interferon-stimulated response elements (ISREs) in the promoter region of HERV-K (HML-2) suggests its expression could be regulated by inflammatory cytokines. (I) LTR-derived chromosomal re-arrangement can induce aberrant expression profile of host genes. Polymorphic integration, a same HERV-K (HML-2) locus showing different status in different individuals, may causing different expression profile of both the viral proteins and their proximal host genes, can be a possible avenue to study the pathogenic functions of HERV-K (HML-2).