Intrinsic Host Defenses Against HIV and Other Retroviruses

Intrinsic host defense: Primates have evolved a number of gene families that limit or restrict retroviral infections. In collaboration with Harmit Malik's lab. We are studying the evolution of function of these intrinsic anti-viral genes. We have found that some of these genes have been rapidly evolving throughout the history of primates and some have been under selective pressure in recent human history.

Trim5α — We have found regions of accelerated evolution in the Trim5α protein and have shown that these are the regions that confer specificity for which viruses can interact with a given Trim5α. While there are nearly no human polymorphisms in the recognition part of Trim5α, there is a very high frequency polymorphism in the human population that renders the effecter part of the protein non-functional.

We recently began a study to find the ancient selective pressures for human Trim5α. We found that human Trim5a is capable of restricting an ancient extinct retroviru, called PtERV1, that is found in the genome of chimpanzees, gorillas, and many old world primates, but is completely missing from the genome of humans. Further resistance to PtERV1 and to HIV seem to be mutually exclusive such that ancient human selection for resistance to PtERV may have rendered modern humans more susceptible to our current pandemic of HIV.

see Publications section for access to the 2007 paper in Science.

Apobec3 — The human Apobec3 locus encodes at least 7 proteins that have cytidine deaminase activity that act against retroviruses. However, this locus has been very dynamic over primate evolution. We have recently shown that one of the proteins, Apobec3H is not expressed in humans, even though the macaque version is active as an anti-retroviral agent. The function of these genes is very dynamic over recent evolutionary history and we would like to understand the consequences of these changes and the pathogens that drove the selections.

Other host defense genes--We are also interested in identifying additional host defense genes and the evolutionary pressures that allow retroviruses to escape them.

Emerman, Michael (2006) Proc. Natl. Acad. Sci. USA 103, 5249-5250
Copyright ©2006 by the National Academy of Sciences