Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis

Abstract

A number of observations have led researchers to postulate that, despite being replication-defective, human endogenous retroviruses (HERVs) may have retained the potential to cause or contribute to disease. However, mechanisms of HERV pathogenicity might differ substantially from those of modern infectious retroviruses or of the infectious precursors of HERVs. Therefore, novel pathways of HERV involvement in disease pathogenesis should be investigated. Recent technological advances in sequencing and bioinformatics are making this task increasingly feasible. The accumulating knowledge of HERV biology may also facilitate the definition and general acceptance of criteria that establish HERV pathogenicity. Here, we explore possible mechanisms whereby HERVs may cause disease and examine the evidence that either has been or should be obtained in order to decisively address the pathogenic potential of HERVs.

Keywords: autoimmunity; cancer; endogenous retrovirus; integrations; mutagenesis; pathogenesis.

Figure 1

Typified retroviral life cycle. Retroviral infection begins with virion attachment usually to a cellular receptor, followed by fusion of virion and plasma membranes. In the cytosol, the two copies of genomic RNA are reverse-transcribed and following capsid disassembly they form the pre-integration complex, which then enters the nucleus. The reverse-transcribed cDNA copy is then integrated into the host cell DNA and from that point this provirus behaves analogously to a cellular gene, in that cellular division of an infected cell will create two infected daughter cells. Expression of mRNA from the provirus provides both new genomic RNAs as well as synthesis of viral proteins, which are all then assembled into new virions. These are then released from the plasma membrane and undergo maturation before they infect the next cell.

Figure 2

Model of retroviral endogenization. Retroviral infection of a germ cell is thought to make integration into the host germ line (denoted by an asterisk) possible. If an infected germ cell develops into offspring, it will transmit its provirus to every single cell of the offspring, akin to inheritance of a host gene. In evolutionary time, germ-line integrated proviruses can either expand in number within the germ-line and in the population, ultimately achieving fixation, or become extinct by random events or selection pressure against them.

Figure 3

Exemplified HERV precursor genomic structure. This proviral structure is based on HERV-K(HML2) proviruses, which are considered the most recently introduced in humans (in the last five million years) and contain the most complete proviral copies, including full-length proviruses, with the most intact open reading frames (ORFs). The proviral LTRs can act as promoters of RNA transcription. Four major ORFs are depicted: gag encoding structural proteins; pro encoding protease; pol encoding RT, RNAse H, and IN domains; and env encoding for the retroviral envelope proteins. A smaller ORF, termed rec, is the functional counterpart of Rev and Rex encoded by more complex retroviruses, such as HIV-1 and HTLV-1, respectively. There appear to be several-hundred copies of proviruses belonging to this particular group in the human genome. However, in addition to very few copies of the near complete structure shown here, the majority harbor deletions ranging from small internal deletions to just solo LTRs, proviruses which have lost, by recombination between the two LTRs, all integral genes, leaving a single LTR sequence.