Scientists Narrow in on Protein That Kills HIV

The finding could lead to new TRIM5-alpha-based treatments that would knock out HIV in humans.

Senior researcher Edward M. Campbell, Ph.D., from Loyola University Health System (Maywood, IL, USA), and colleagues reported their findings in an article online in August 2010 and published in the September 15, 2010, issue of the journal Virology. In 2004, other researchers reported that TRIM5a protects rhesus monkeys from HIV. The TRIM5a protein (tripartite motif-containing protein 5) first latches on to a HIV virus, then other TRIM5a proteins gather and destroy the virus.

Humans also have TRIM5a, but whereas the human version of TRIM5-alpha protects against some viruses, it does not protect against HIV. Researchers hope to convert TRIM5-alpha into an effective therapeutic agent. First, they need to identify the components in TRIM5-alpha that enable the protein to kill viruses. "Scientists have been trying to develop antiviral therapies for only about 75 years,” Dr. 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.”

TRIM5-alpha consists of nearly 500 amino acid subunits. Loyola researchers have identified six individual amino acids, located in a previously little-examined region of the TRIM5-alpha protein, that are crucial in the ability of the protein to inhibit viral infection. When these amino acids were altered in human cells, TRIM5-alpha lost its ability to inhibit HIV-1 infection. (The research was performed on cell cultures; no rhesus monkeys were used in the study.)

By continuing to zero in on their search, researchers hope to identify an amino acid, or combination of amino acids, that enable TRIM5-alpha to destroy HIV. Once these key amino acids are identified, it might be possible to modify genetically TRIM5-alpha to make it more effective in humans. Moreover, a better determination of the underlying mechanism of action might enable the development of drugs that mimic TRIM5-alpha action, according to Dr. Campbell.

In their study, scientists used Loyola's US$225,000 wide-field deconvolution microscope to observe how the amino acids they identified changed the behavior of TRIM5-alpha. They attached fluorescent proteins to TRIM5-alpha, in essence, to make it glow. In current research, researchers are fluorescently labeling individual HIV viruses and measuring the microscopic interactions between HIV and TRIM5-alpha.

Dr. Campbell is an assistant professor in the department of microbiology and immunology at Loyola University Chicago Stritch School of Medicine.

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