MRC National Institute for Medical Research, London

Science for Health

The structure of Nijmegen-breakage syndrome protein 1

Main navigation

Home
News

News & events

News
- Archive

Lentivirus host cell interactions, older than we thought

16 September 2010

NIMR scientists studying fossil retroviruses have demonstrated that interaction with the host cell factor, cyclophilin A, has been a fundamental aspect of lentiviral replication for more than twelve million years. The research is published in Cell Host and Microbe.

Throughout evolution, mammalian genomes have been exposed to invading retroviruses that in many instances have been incorporated into the germ line becoming endogenous retroviruses. The lentiviral family of retroviruses are found in primates and some other mammals. They are the etiological agents of chronic diseases often associated with immunodeficiency and are characterised by long incubation periods. Although germ line integration is commonplace in many other retroviral genera it was thought that this property did not extend to the lentiviruses and that they were entirely exogenous. The recent discovery of prehistoric endogenous lentiviruses in rabbits (RELIK) and lemurs (PSIV) refuted these ideas and revealed that lentiviruses have a much wider host-range, are capable of germ-line integration and are far more ancient than previously thought.

Another feature particular to some lentiviruses is their interaction with the host cell protein, cyclophilin-A (CypA). HIV-1 and other lentiviruses contain substantial quantities of CypA, bound to the retroviral capsid protein (CA), in a region referred to as the CypA binding loop. Other studies have demonstrated the viral dependency on the CypA-CA interaction as inhibition results in a reduction in HIV-1 infectivity in certain cell types. Conversely, some cellular restriction factors exploit the CypA-CA interaction by employing CypA domains to recognise and target the invading virus in defence mechanisms that prevent proviral integration.

The research groups of Ian Taylor (pictured), from NIMR’s Division of Molecular Structure, Willie Taylor, from the Division of Mathematical Biology, and Jonathan Stoye, from the Division of Virology, used DNA sequences from the gag genes of prehistoric endogenous lentiviruses to reconstruct ancient/modern chimeric lentiviruses. These viruses containing ancient capsids can infect both dividing and non-dividing cells and are also targeted by present-day host-cell restriction factors.

Further structural and functional analyses of ancient capsid proteins revealed that these prehistoric viruses contain many of the features found in modern day lentiviruses, including the CypA-binding loop previously only associated with HIV-1. Together, these studies reveal the existence of cyclophilin dependence in ancient retroviruses and show that the CypA-CA interaction is a widespread lentiviral characteristic, predating the emergence of HIV-1 by some twelve million years. Moreover, this fundamental interaction has been preserved throughout lentiviral evolution even at the cost of exposing the virus to cellular restriction factors providing evidence for an antagonistic relationship between ancient lentiviruses and cellular restriction factors during the Miocene and Pliocene ages.

RELIK-CypA complex and structure-based retroviral phylogeny

Click image to view at full-size

Crystal structures (ribbons representation) of the RELIK CA-NtD-CypA (upper) and the HIV-1 CA-NtD-CypA (lower) complexes. The left-hand panel is a phylogenetic tree derived from the structural similarity of the capsid protein. Four genera of retroviruses are included in the dendrogram.

This ancient capsid-cyclophilin interaction is fundamental to successful lentiviral infection and predates the emergence of HIV-1 by over 12 million years.

Ian Taylor