'There and back again': revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

Abstract

Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation.

Keywords: HERV-K; endogenous retroviruses; pathogenesis; pathophysiology.

Figure 1.

Population genetics of endogenous retroviruses. It has been suggested that ERVs that we currently identify in animal genomes are the result of ancient retroviral epidemics. Thus, the first step of ERV colonization involves the establishment of an epidemic in a susceptible population. Endogenization starts when retroviruses integrate into the host's germline and pass to the offspring through inheritance. The copies of the ERV in the germline constitute a family and may increase through time (ERV activity). Some of these copies become extinct or drift to fixation (i.e. every individual has the same locus).

Figure 2.

The fate of ERV long terminal repeats (LTRs). When a retrovirus integrates in the host's genome (time 0), LTRs are identical. Over time, they accumulate mutations at a host's substitution rate; thus the divergence of the LTRs from the same locus can be used to estimate how much time has passed since integration. On many occasions, a host genomic repair mechanism uses LTRs from a locus as a template to loop-out the internal region of the ERV resulting in remnant LTRs known as solo-LTRs. (Online version in colour.)

Figure 3.

Model of ERV upregulation with respect to disease. HK2 RNA has been isolated from the plasma of patients with lymphoma and breast cancer. It is thought that upregulation of HK2 in these diseases could be connected with genomic instability which, however, affects most of the mobile elements. HK2 is isolated from the plasma because it is a re-infecting ERV and can form retrovirus-like particles.