From the archive, originally posted by: [ spectre ]

Science 22 June 2007:
Vol. 316. no. 5832, pp. 1756 – 1758
DOI: 10.1126/science.1140579

Restriction of an Extinct Retrovirus by the Human TRIM5{alpha}
Antiviral Protein
Shari M. Kaiser,1,2 Harmit S. Malik,3 Michael Emerman2,3*

Primate genomes contain a large number of endogenous retroviruses and encode evolutionarily dynamic proteins that provide intrinsic immunity to retroviral infections. We report here the resurrection of the core protein of a 4-million-year-old endogenous virus from the chimpanzee genome and show that the human variant of the intrinsic immune protein TRIM5{alpha} can actively prevent infection by this virus. However, we suggest that selective changes that have occurred in the human lineage during the acquisition of resistance to this virus, and perhaps similar viruses, may have left our species more susceptible to infection by human immunodeficiency virus type 1 (HIV-1).
Ancient trade-off may explain why humans get HIV
Roxanne Khamsi  /  21 June 2007

A protein that protected our human ancestors against a virus that ravaged other primates may now be responsible for our susceptibility to HIV, a new study suggests. The discovery could help scientists predict which viruses found in other species are most likely to cross over and lethally infect humans. The idea that early humans had an immune system that differed from other primates first came about after biologists sequenced the chimp genome. The chimp sequence contains 130 copies of a virus called Pan troglodytes endogenous retrovirus, or PtERV1. Retroviruses often have the ability to insert themselves into an organism’s DNA. But PtERV1 is completely absent from the human genome.

Reviving ancient life
Studies have also shown that the human version of an antiviral protein called TRIM5-alpha differs dramatically to the version of this protein found in other primate species. TRIM5-alpha offers immune protection by binding to virus-containing capsules inside cells and prompting their destruction. Michael Emerman at the Fred Hutchinson Cancer Research Center in Seattle, US, and colleagues decided to test whether our unique version of TRIM5-alpha could explain why PtERV1 did not invade our genome. The team generated TRIM5-alpha from human, chimp and gorilla genes in order to see how well various versions of the protein protected against PtERV1 in cat cells grown in a laboratory dish. There was one problem though: active versions of PtERV1 no longer exist and the copies of this retrovirus found in primate DNA are woefully degraded. So Emerman’s team looked for commonalities among the chimp versions of the virus to partly reconstruct the ancient form of PtERV1. From this ancient sequence they produced part of the PtERV1-containing capsule, and attached it to a harmless mouse virus.

HIV vulnerability
About 4% of the cat cells exposed to this resurrected PtERV1 capsule combination became infected within a day. And those cat cells that also contained the gorilla version of TRIM5-alpha did no better.But human TRIM5-alpha protected the cat cells, leaving them 100 times less susceptible to PtERV1 infection – only 0.04% of the cells became infected. On the flipside, Emerman notes that the human version of TRIM5 alpha does not recognise the capsule containing HIV inside cells, whereas other primate versions of this protein can.

Non-human primates do not normally get infected with HIV. So he speculates that the same attributes of TRIM5-alpha that make it effective against PtERV1 might explain why it cannot bind and destroy HIV. Emerman suggests that monitoring how well the human version of TRIM5- alpha protects against viruses related to HIV, could help scientists predict which pathogens have the potential to cross into our species from other primates.

Journal reference: Science (DOI: 10.1126/science.1140579)

FHCRC Director: Michael Emerman, PhD
E-mail: memerman [at] fhcrc [dot] org
The Emerman lab studies the regulatory and structural genes of the human immunodeficiency virus (HIV) in order to understand the molecular basis for its replication and pathogenic properties. Because the virus requires host cell proteins to complete nearly every step of it lifecycle, much of our focus is on identifying and characterizing host cell functions that are modified or utilized by viral proteins to serve specific functions for viral replication.

Shari M. Kaiser,1,2 Harmit S. Malik,3 Michael Emerman2,3*
1 Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

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