Researchers Discover How TRIM5 Protects against HIV

SUMMARY The TRIM5 protein protects against HIV infection in monkeys by attaching to the virus capsid and triggering an antiviral immune response.

TRIM5 is a protein that plays a role in limiting infection by targeting HIV and other retroviruses as they enter host cells. TRIM5 in certain monkey species prevents infection, but human TRIM5 does not have such a strong protective effect.

As described in the April 21, 2011 issue of Nature, researchers have now elucidated the mechanism by which TRIM5 recognizes and interferes with HIV, which may lead to new therapeutic approaches.

Below is an edited excerpt from a press release issued by the University of Zurich describing the research and its findings.

How TRIM5 Fights HIV

Structure of the latticed shell of the HI virus. (image courtesy of University of Zurich).

April 20, 2011 -- Thanks to a certain protein, rhesus monkeys are resistant to HIV. Known as TRIM5, the protein prevents [HIV] from multiplying once it has entered the cell. Researchers from the universities of Geneva and Zurich have now discovered the protein's mechanism, as they report in Nature. This also opens up new prospects for fighting HIV in humans.

Unlike people, certain monkey species, such as rhesus or night monkeys, are resistant to HIV thanks to TRIM5, a cellular protein. In the case of an HIV infection, the protein intercepts the virus as soon as it enters the cell and prevents it from multiplying. We have known about TRIM5 for over six years. However, the mechanism TRIM5 uses to prevent [HIV] from multiplying was still largely unknown.

The majority of the key aspects of TRIM5's defense mechanism against HIV was discovered by the Swiss research teams of Prof. Jeremy Luban, University of Geneva, and Prof. Markus Grütter, University of Zurich, in collaboration with teams from the USA and France. They demonstrated that TRIM5 immediately triggers an immune response if infected with HIV. Consequently, TRIM5 is an HIV sensor in the innate immune system. Unlike the adaptive immune system, which only develops when confronted with a pathogen, the innate immune system is already able to eliminate pathogens as soon as it comes into contact with them.

[HIV], which penetrates the cell during an infection, has a shell, the components of which are arranged in a lattice, similar to the pattern on a soccer ball. TRIM5 recognizes this lattice structure and specifically attaches itself to it. This stimulates the protein to produce signal molecules known as polyubiquitin chains in the cell. These chains immediately trigger an anti-viral reaction. The "alerted" cell can then start eliminating cells infected with HIV by releasing messenger substances (cytokines).

Humans also have a TRIM5 protein, but it is less effective in fending off HIV. However, the findings in resistant monkeys have opened up new possibilities and ways of fighting HIV in humans. 33 million people are currently infected with HIV worldwide; two million die of AIDS each year. And with 2.7 million people becoming infected every year, HIV remains a major problem.

Investigator affiliations: Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland; Department of Biochemistry, University of Zurich, Zurich, Switzerland; Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT; Novimmune SA, Geneva, Switzerland; Institut Pasteur, Inserm U818, Paris, France.

4/26/11

Reference
T Pertel, S Hausmann, D Morger, et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472(7343):361 (abstract). April 21, 2011.

Other Source
University of Zurich. How TRIM5 fights HIV. Press release. April 20, 2011.