Retroviral influence on human embryonic development

EmbryogenesisAbout eight percent of human DNA is viral: it consists of retroviral genomes produced by infections that occurred many years ago. These endogenous retroviruses are passed from parent to child in our DNA. Some of these viral genomes are activated for a brief time during human embryogenesis, suggesting that they may play a role in development.

There are over 500,000 endogenous retroviruses in the human genome, about 20 times more than human genes. They were acquired millions of years ago after retroviral infection. In this process, viral RNA is converted to DNA, which then integrates into cell DNA. If the retroviral infection takes place in the germ line, the integrated DNA may be passed on to offspring.

The most recent human retroviral infections leading to germ line integration took place with a subgroup of human endogenous retroviruses called HERVK(HML-2). The human genome contains ~90 copies of these viral genomes, which might have infected human ancestors as recently as 200,000 years ago. HERVs do not produce infectious virus: not only is the viral genome silenced – no mRNAs are produced – but they are littered with lethal mutations that have accumulated over time.

A recent study revealed that HERVK mRNAs are produced during normal human embryogenesis. Viral RNAs were detected beginning at the 8-cell stage, through epiblast cells in preimplantation embryos, until formation of embryonic stem cells (illustrated). At this point the production of HERVK mRNA ceases. Viral capsid protein was detected in blastocysts, and electron microscopy revealed the presence of virus-like particles similar to those found in reconstructed HERVK particles. These results indicate that retroviral proteins and particles are present during human development, up until implantation.

Retroviral particles in blastocysts are accompanied by induction of synthesis of an antiviral protein, IFITM1, that is known to block infection with a variety of viruses, including influenza virus. A HERVK protein known as Rec, produced in blastocysts, binds a variety of cell mRNAs and either increases or decreases their association with ribosomes.

Is there a function for HERVK expression during human embryogenesis? The authors speculate that modulation of the ribosome-binding activities of specific cell mRNAs by the viral Rec protein could influence aspects of early development. As Rec sequences are polymorphic in humans, the effects could even extend to individuals. In addition, HERVK induction of IFITM1 might conceivably protect embryos against infection with other viruses.

The maintenance of open reading frames in HERV genomes, over many years of evolution, suggests a functional role for these elements. Evidence for such function comes from the syncytin proteins, which  are essential for placental development: the genes encoding these proteins originated from HERV glycoproteins. However, not all endogenous retroviruses are beneficial: a number of malignant diseases have been associated with HERV-K expression.

TWiV 279: The missing LNC

On episode #279 of the science show This Week in Virology, Vincent, Alan, and Kathy reveal how a retrovirus in the human genome keeps embryonic stem cells in a pluripotent state, from where they can differentiate into all cells of the body.

You can find TWiV #279 at www.microbe.tv/twiv.

TWiV 272: Give peas a chance

On episode #272 of the science show This Week in Virology, the TWiV team describes aphid control by using a viral capsid protein to deliver a spider toxin to plants, and a human endogenous retrovirus that enhances expression of a neuronal gene.

You can find TWiV #272 at www.microbe.tv/twiv.

TWiV 218: Monkeys turning valves and pushing buttons

On episode #218 of the science show This Week in Virology, Vincent, Alan, and Welkin discuss how endogenous retroviruses in mice are held in check by the immune response.

You can find TWiV #218 at www.microbe.tv/twiv.

TWiV 129: We’ve got mail

rich unwindsHosts: Vincent Racaniello, Alan Dove, Dickson Despommier, and Rich Condit

Vincent, Alan, Dickson and Rich answer listener questions about XMRV, yellow fever vaccine, virus-like particles, West Nile virus, amyotrophic lateral sclerosis and human endogenous retroviruses, multiplicity of infection, and how to make a poxvirus.

Click the arrow above to play, or right-click to download TWiV #129 (67 MB .mp3, 93 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

Weekly Science Picks

Rich – Polyxeni Potter and EID covers
Dickson – American Museum of Natural History
Alan –
Moon Trees (EurekAlert! article)
Vincent – Infection Landscapes

Listener Picks of the Week

Didier  – The Vaccines (MySpace)
/Sven-Urban –
The Science of Discworld by Terry Pratchett
GarrenOmega Tau podcast

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

TWiV 122: More fun than a monkey full of viruses

japanese macaquesHosts: Vincent Racaniello, Dickson Despommier, Alan DoveRich Condit, and Welkin Johnson

On episode #122 of the podcast This Week in Virology, the complete TWiV crew teams up with Welkin Johnson to explore the other AIDS epidemic, infection of monkeys with simian immunodeficiency virus, and its restriction by the cellular protein TRIM5.

Click the arrow above to play, or right-click to download TWiV #122 (77 MB .mp3, 147 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

Weekly Science Picks

Welkin – Supramap
Dickson – Science issue on visualizing data
Rich – Doonesbury weighs in on vaccines and autism

Alan – US National Vaccine Plan
Vincent – US Supreme Court decision on vaccine litigation (NY Times)

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

TWiV 93: Our infectious inbox

Hosts: Vincent Racaniello, Alan Dove, and Rich Condit

On episode #93 of the podcast This Week in Virology, Vincent, Alan, and Rich answer listener questions about lab procedures, prokaryotes, endogenous retroviruses, the iPad and teaching, prions, mimivirus, splitting water with viruses, and the polio outbreak in Tajikistan.

Click the arrow above to play, or right-click to download TWiV #93 (76 MB .mp3, 105 minutes)

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, or by email, or listen on your mobile device with Stitcher Radio.

Links for this episode:

Weekly Science Picks

Alan – Southern Fried Science
Rich –
Tree of Life web project
Vincent – Dickson Despommier at Big Think

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv or leave voicemail at Skype: twivpodcast. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

TWiV 91: You’re an ERVous wreck

Hosts: Vincent Racaniello, Dickson DespommierAlan Dove, Rich Condit, and Welkin Johnson

On episode #91 of the podcast This Week in Virology, Vincent, Dickson, Alan, Rich and Welkin discuss the nature, origin, and evolution of endogenous retroviruses (ERVs), and the recent finding of endogenous filovirus genomes in mammals.

Click the arrow above to play, or right-click to download TWiV #91 (64 MB .mp3, 89 minutes)

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, or by email, or listen on your mobile device with Stitcher Radio.

Links for this episode:

Weekly Science Picks

Welkin – Advice for a Young Investigator by Santiago Ramon y Cajal
Rich –
How microbes define and defend us
Dickson – H1N1 virus lacks 1918 virus killer protein
Alan –
The Xtal Set Society
Vincent – Antibodies and the quest for an AIDS vaccine

Send your virology questions and comments (email or mp3 file) to twiv@microbe.tv or leave voicemail at Skype: twivpodcast. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

A retrovirus is invading the Koala genome

friendly-male-koalaThere are 62 koalas in Japanese zoos, and 50 of them are infected with koala retrovirus (KoRV). Infection may lead to leukemia and lymphoma, which could negatively impact Koala populations. What is the origin of KoRV?

The koala is native to Australia where they are found in eastern and southern coastal areas. All koalas in the eastern state of Queensland are infected with KoRV, while there are still some uninfected animals in the south. In particular, the koalas on Kangaroo Island do not carry the virus. Koalas were imported to Kangaroo Island in the early 1900s, and apparently those animals were free of KoRV. The island is 8 miles offshore which may contribute to the absence so far of the virus. However, the koalas sent to Japanese zoos likely carried KoRV.

Curiously, 38 koalas have been born in Japanese zoos since the original importation, and 36 of these animals are infected with KoRV. This high rate of infection is a consequence of the fact that KoRV DNA integrates into DNA of koala germ cells. The viral genome is transmitted vertically, from mother to offspring.

The nucleic acid of retroviruses is RNA, but it is converted to a DNA copy during infection and integrates into host cell DNA. If the viral DNA integrates into the germ line, then it can remain in the organism for many generations. The genomes of most higher organisms contain remnants of retroviral genomes called endogenous retroviruses (ERVs). In primates these infections appear to have occurred millions of years ago; in humans, they comprise 6-8% of the genome, more than protein coding sequences (1-2%)! Most ERVs are defective but the koala ERVs are unique because they appear to produce viral particles.

No one has ever observed germ-line infection of a species with retroviruses – until infection of koalas with KoRV was discovered.  This process of ‘endogenization’ can now be studied in real time.

When did the KoRV begin invading the koala genome? It has been suggested that the initial infection occurred less than 100 years ago, but examination of preserved Koala DNA will be required to confirm this estimate.

The origin of most ERVs is unknown because the original infecting viruses disappeared long ago. But it might be feasible to identify the precursor of KoRV, which entered the genome relatively recently. KoRV appears to be closely related to an ERV of the Asian mouse Mus caroli. If this relationship is correct it will have to be determined how the virus was transmitted from mice in Southeast Asia to koalas in Australia.

Infection with KoRV in captive animals may lead to fatal lymphomas or immunosuppression and chlamydial infection. It is possible that infection of wild animals might lead to further decreases in this dwindling population. Should a KoRV vaccine developed to prevent extinction? Development and testing of a vaccine would require the use of koalas. It’s a difficult question, because the spread of KoRV among koalas is a natural part of evolutionary selection. Should we interfere?

Stoye, J. (2006). Koala retrovirus: a genome invasion in real time Genome Biology, 7 (11) DOI: 10.1186/gb-2006-7-11-241

Tarlinton, R., Meers, J., & Young, P. (2006). Retroviral invasion of the koala genome Nature, 442 (7098), 79-81 DOI: 10.1038/nature04841