Two years ago, TRIM5 was shown to be a potent, cytoplasmic inhibitor of infection by retroviruses, including HIV-1. Since then, there has been an explosion of papers providing genetic evidence that the carboxy-terminal SPRY domain of TRIM5alpha is required for specific recognition of the viral capsid. Our paper is the first to confirm this prediction using biochemical methods.

“We have demonstrated that human cells possess a protein (TRIM5alpha) which has evolved to bind and inactivate the core of invading retroviruses.”

Conventional biochemical approaches by many groups failed to reveal TRIM5alpha binding to viral capsid. Sarah Sebastian, the graduate student who did the very clean and convincing experiments, demonstrated binding to TRIM5 in a SPRY-domain and capsid-specific manner by using intact virion cores. Sarah’s choice of experimental conditions was a successful synthesis of ideas and methods from the retrovirus biochemical literature.

We have demonstrated that human cells possess a protein (TRIM5alpha) which has evolved to bind and inactivate the core of invading retroviruses.

For about 15 years we have been attempting to identify host factors that regulate HIV-1 infection. Since our discovery 13 years ago that HIV-1 capsid interacts with a cellular protein called cyclophilin A, we have attempted to understand how this factor regulates HIV-1 infectivity.

In the course of these efforts, a screen of owl monkey cDNA by graduate student David Sayah discovered that HIV-1 infection is blocked by a TRIM5-cyclophilin A fusion protein expressed in this species (Nature 430:569). An independent screen by graduate student Matt Stremlau in the lab of Joe Sodroski discovered that rhesus macaque TRIM5alpha is an HIV-1 inhibitor (Nature 427:848).

Social: In 2006, AIDS is still a huge pandemic. Any information concerning virus replication or virus-host interactions has the potential to yield new treatments or preventive measures that might tilt the balance in a favorable direction.

Political: The experiments described above were funded by the NIH, through investigator-initiated RO1s. Until now, no country has been able to match the creative, independent research that has been possible in the USA. Current government policies concerning research funding, education, and immigration threaten to put an end to this proud tradition.