Endogenous retrovirus



Endogenous retroviruses (ERVs) are sequences in the genome thought to be derived from ancient viral infections of germ cells in humans, mammals and other vertebrates; as such their proviruses are passed on to the next generation and now remain in the genome.

Hypothesis of origin
Endogenous retroviruses may be a variant of a retrovirus which became permanently integrated with its host and is inherited from generation to generation as part of the genome of the host.

Retroviruses are single-stranded RNA viruses that reverse-transcribe their RNA into DNA for integration into the host's genome. Most retroviruses (such as HIV-1) infect somatic cells, but in very rare cases, it is thought that exogenous retroviruses have infected germline cells (cells that make eggs and sperm) allowing integrated retroviral genetic sequences to be passed on to subsequent progeny, thereby becoming 'endogenous'. Endogenous retroviruses have persisted in the genome of their hosts for thousands of years. However, they are generally only infectious for a short time after integration as they acquire many inactivating mutations during host DNA replication. They can also be partially excised from the genome by a process known as recombinational deletion. They are thought to play a key role in evolution. Some human ERVs have been implicated in ALS, certain autoimmune diseases, and cancers.

Human endogenous retroviruses
Human endogenous retroviruses (HERVs) are suspected of involvement in some autoimmune diseases, in particular with multiple sclerosis. In this disease, there appears to be a specially associated member of the family of human endogenous retrovirus W known as "MS-associated retrovirus" (MSRV).

Thousands of endogenous retroviruses exist in human DNA. HERVs make up 98,000 elements and fragments—nearly 8%—of the human genome. According to a study published in 2005, no HERVs capable of replication had been identified; all appeared to be defective, containing major deletions or nonsense mutations. This is because most HERVs are merely traces of original viruses, having first integrated millions of years ago. However, one family of viruses has been active since the divergence of humans and chimpanzees. This family, termed HERV-K (HML2), makes up less than 1% of HERV elements but is one of the most studied. There are indications it has even been active in the past few hundred thousand years, e.g., some human individuals carry more copies of the virus family than others. Traditionally, age estimates of HERVs are performed by comparing the 5' and 3' LTR of a HERV; however, this method is only relevant for full-length HERVs. A recent method called cross-sectional dating uses variations within a single LTR to estimate the ages of HERV insertions. This method is more precise in estimating HERV ages and can be used for any HERV insertions. Cross-sectional dating has been used to suggest that two members of HERV-K(HML2), HERV-K106, and HERV-K116 were active in the last 800,000 years and that HERV-K106 may have infected modern humans 150,000 years ago. However, the absence of known infectious members of the HERV-K(HML2) family, and the lack of elements with a full coding potential within the published human genome sequence, suggests to some that the family is less likely to be active at present.

In 2004 it was reported that antibodies to HERVs were found in greater frequency in the sera of people with schizophrenia. Additionally, the cerebrospinal fluid of people with recent onset schizophrenia contained levels of a retroviral marker, reverse transcriptase, four times higher than control subjects. Researchers continue to look at a possible link between HERVs and schizophrenia, with the additional possibility of a triggering infection inducing schizophrenia.

In 2006, researchers led by Thierry Heidmann at the Institut Gustave Roussy in Villejuif, France, were able to recreate a HERV, which they dubbed Phoenix.

In 2007, a group led by Doug Nixon and Keith Garrison at the University of California, San Francisco, and by Mario Ostrowski and Brad Jones at the University of Toronto, published a study providing evidence for T cell immune responses against HERVs in HIV-infected individuals. The group hypothesized that HIV induces HERV expression in HIV infected cells, and that a vaccine targeting HERV antigens could therefore specifically eliminate HIV infected cells. The potential advantage of this novel approach is that, by using HERV antigens as surrogate markers of HIV infected cells, it could circumvent the difficulty inherent in directly targeting notoriously diverse and fast-mutating HIV antigens.