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HIV Thrives on Human Host Proteins

New findings open HIV research

By Molly Polen | 12.14.2009
Originally Published July 2008
Blood samples

In February 2008, researchers from Harvard Medical School and the Howard Hughes Medical Institute (HHMI) identified 273 human proteins that HIV needs to thrive. This landmark discovery, published in Science magazine, opens new opportunities for scientists to fight the virus using therapeutic targets.

Since HIV makes only 15 of its own proteins, it must commandeer human cell proteins for successful infection. A key advantage to using these host proteins as therapeutic targets, the researchers say, is that the proteins are essential for functions that HIV cannot manage on its own. These host proteins are active in HIV’s life cycle, helping it gain access to the cell, to integrate itself into the cell’s genome, replicate and leave the cell to infect other cells.

“If we could make drugs to host cell proteins, they are unlikely to be overcome by HIV. The virus would have to evolve a new ability, and that’s not very likely,” says lead researcher Stephen J. Elledge, PhD, the Gregor Mendel Professor of Genetics and professor of medicine at Harvard Medical School, and an HHMI investigator.

Of the 273 proteins identified in the study, only 36 were previously known to investigators. The 237 newly pinpointed proteins could help researchers devise better treatment strategies to get around a major HIV treatment issue: the virus mutating to develop resistance to antiviral drugs.

In the study, Elledge and his team used a technique known as RNA interference to turn off genes in cells. Their first experiments shut off genes four at a time. Later experiments narrowed the focus to individual genes. The researchers then exposed the cells to HIV to see how the virus handled the absence of each host cell protein to eliminate the nonessential ones and to learn which ones were vital.

Many of the host proteins identified by the team are more frequent in immune cells than other types of human cells. This helps explain why HIV is so difficult to treat—it takes over the very immune cells that the body needs to fight infection.

The disadvantage of targeting these proteins, of course, is that blocking human proteins could prevent functions that are important for normal living and could result in serious side effects. However, there is precedent for this type of approach. Some cancer therapies work in a similar way by blocking the proteins that feed the fast-growing tumor cells without killing many other fast-growing cells, such as those in the bone marrow.

The techniques used by the Harvard group could be used to expose vulnerabilities in other viruses, such as hepatitis, which may rely on some of the same proteins identified in this study.

“We’re closing in on a systems-level understanding of HIV, which opens new therapeutic avenues,” says Elledge. “We might be able to tweak various parts of the system to disrupt viral propagation without making our own cells sick.”