Human endogenous retroviruses in health and disease: a symbiotic perspective

Abstract

In the early 1970s, scientists scanning baboon placentas with the electronmicroscope were startled to discover endogenous retroviruses budding from the syncytiotrophoblast. Similar viruses were subsequently detected in the placentas of healthy cats, mice, guineapigs and humans.1 Retroviruses were originally discovered when Peyton Rous noticed the effects of the avian sarcoma virus in 1910, but their infectious and pathogenic potential for humans only became clear with the discoveries of the sexually transmitted human T-cell leukaemia viruses, HTLV-I and HTLV-II, and even more so with the arrival of the human immunodeficiency viruses, notably HIV-1, which ushered in the lethal pandemic now underway. The genomes of retroviruses are based on RNA. To insert themselves into the DNA-based genome of humans they possess a unique enzyme, reverse transcriptase (RT), that copies the viral RNA template to its complementary DNA, which is then integrated into the chromosomes. Retroviruses have two very different life strategies. Exogenous retroviruses, like HIV, reproduce within the somatic tissues of infected individuals and spread in the human population through sexual intercourse and contaminated blood products as well as from mother to child by passage of virus transplacentally or during parturition, or via breast milk. Although it is likely that the HTLV and HIV viruses first infected humans through cross-species spread from animal hosts, their natural host is now the human species. Endogenous retroviruses (ERVs) have invaded the germ cell lines of every species of vertebrate. Here they replicate in Mendelian fashion, as an integral part of the sexual reproduction of the host, to inhabit the genome of all future generations. This is known as germline transmission. It has important evolutionary, physiological and pathological implications. Genome sequencing reveals that 8% of the human genome consists of human endogenous retroviruses, or HERVs, and, if we extend this to HERV fragments and derivatives, the retroviral legacy amounts to roughly half our DNA.2,3 Although many HERVs have been degraded into fragments, they are still readily identifiable from the presence of any of three pathognomonic genes, gag, pol and env, and their flanking long terminal repeats or LTRs (see Figure 1). These genes, which they share with HTLV and HIV, are subdivided into regions with different functions. For example, the env gene codes for the surface protein of the virus as well as regions responsible for inducing human cell fusion and immunosuppression. Tens of thousands of HERVs have entirely lost their genes, leaving a legacy of vast numbers of solitary LTRs that still retain a variety of genetic potentials. Human endogenous retroviruses are believed to be the legacy of ancient germ cell infections by exogenous retroviruses, dating from 60 million years ago to the present. Pandemic plagues are a brutal manifestation of an evolutionary mechanism resulting in changes to the species gene pool I have labelled 'plague culling'. Assuming that the exogenous forebears of our human endogenous retroviruses once behaved as highly contagious infections, following transmission pathways akin to that of HIV-1, their potential for pandemic spread through the original African-based population of primates and subsequently hominids implies a protracted series of invasions with repeated large-scale attrition. It is salutary to realize that we modern humans are descended from the survivors of this terrible evolutionary legacy. The most recently integrated human endogenous retrovirus yet discovered is HERV-K113, found on chromosome 19 in just 29% of people of mainly African, Asian and Polynesian extraction. It could only have been incorporated into the human genome after the last great migration from Africa, certainly less than 200 000 years ago and possibly much more recently.4 Like the virus designated HERV-H/RGH-2, which is associated with multiple sclerosis, it may retain some degree of horizontal transmissibility.5 However, the great majority of HERVs have lost the capacity for horizontal transmission and have entered into a long-standing union with the rest of the human genome. Figure 1 Geonomic structure of a human endogenous retrovirus