Using a $225,000 microscope, researchers have identified the key components of a protein called TRIM5α that destroys HIV in rhesus monkeys.
The finding could lead to new TRIM5α-based treatments that would knock out HIV in humans, said senior researcher Edward M. Campbell, PhD, of Loyola University Health System.
Campbell and colleagues report their findings in an article featured on the cover of the Sept. 15, 2010 issue of the journal Virology, now available online.
In 2004, other researchers reported that TRIM5α protects rhesus monkeys from HIV. The TRIM5α protein first latches on to a HIV virus, then other TRIM5α proteins gang up and destroy the virus.
Humans also have TRIM5α, but while the human version of TRIM5α protects against some viruses, it does not protect against HIV.
Researchers hope to turn TRIM5α into an effective therapeutic agent. But first they need to identify the components in TRIM5α that enable the protein to destroy viruses. "Scientists have been trying to develop antiviral therapies for only about 75 years," Campbell said. "Evolution has been playing this game for millions of years, and it has identified a point of intervention that we still know very little about."
TRIM5α consists of nearly 500 amino acid subunits. Loyola researchers have identified six 6 individual amino acids, located in a previously little-studied region of the TRIM5α protein, that are critical in the ability of the protein to inhibit viral infection. When these amino acids were altered in human cells, TRIM5α lost its ability to block HIV-1 infection. (The research was done on cell cultures; no rhesus monkeys were used in the study.)
By continuing to narrow their search, researchers hope to identify an amino acid, or combination of amino acids, that enable TRIM5α to destroy HIV. Once these critical amino acids are identified, it might be possible to genetically engineer TRIM5α to make it more effective in humans. Moreover, a better understanding of the underlying mechanism of action might enable the development of drugs that mimic TRIM5α action, Campbell said.
In their research, scientists used Loyola's wide-field "deconvolution" microscope to observe how the amino acids they identified altered the behavior of TRIM5α. They attached fluorescent proteins to TRIM5α to, in effect, make it glow. In current studies, researchers are fluorescently labeling individual HIV viruses and measuring the microscopic interactions between HIV and TRIM5α.
"The motto of our lab is one of Yogi Berra's sayings -- 'You can see a lot just by looking,'" Campbell said.
Campbell is an assistant professor in the Department of Microbiology and Immunology at Loyola University Chicago Stritch School of Medicine. His co-authors are Jaya Sastri, a Stritch graduate student and first author; Christopher O'Connor, a former post-doctorate researcher at Stritch; Cindy Danielson and Michael McRaven of Northwestrn University Feinberg School of Medicine and Patricio Perez and Felipe Diaz-Griffero of Albert Einstein College of Medicine.
The study was supported by a grant from the National Institutes of Health.
Journal
Virology