A completely new target for fighting HIV infection?

Target involves DNA repair genes

Investigators have discovered a natural host defense against HIV thanks to a little help from yeast virus research. Researchers have found that two DNA repair genes can defend cells from HIV infection.1

The DNA repair genes are XPB and XPD, which are major pathways for destroying HIV, says Richard Fishel, PhD, a professor of molecular virology, immunology, and medical genetics and a professor of human cancer genetics at the Ohio State University Comprehensive Cancer Center in Columbus, OH.

The study found that HIV cDNA had greater stability in mutant XPB and XPD cells, which suggests that XPB and XPD could play an important role in defending against HIV infection.1

The key to this discovery was having the flexibility to look at yeast research, Fishel says. Yeast can be infected with a TY1 virus that has some similarities to HIV, he explains. With yeast, investigators earlier had set up a genetic selection to determine which host genes will impact the selection of TY1, Fishel says.

"The problem with TY and yeast is it’s really hard to figure out the mechanism for how this works," Fishel says. "But the research conclusion was that when you knock out these DNA repair genes, you get elevated integration of TY, so they must defend against TY integration."

Fishel recalled the TY1 findings later when he heard of another researcher’s work in studying HIV integration into DNA. By taking the yeast research ground work and seeing if the cell lines discovered in the earlier investigations would have an effect on HIV, HIV investigators were able to find out how the integration process works with HIV, Fishel says.

The reverse transcribed RNA is called cDNA, and for the integration of HIV, cDNA is an obligatory step in the life cycle, because if the virus does not integrate, nothing happens, Fishel says.

"HIV injects RNA into the cell and as it gets into the cytoplasm inside the cell, it takes RNA and copies it into DNA by reverse transcription," Fishel explains. The result is cDNA. "So the cDNA gets into the nucleus and pathway that involves the genes and degrades DNA before it gets into the genome," Fishel explains.

"The majority of cDNA is degraded or lost, and [little] more than 10% of cDNA can ever integrate into the virus, so the majority is lost by some mechanism, and we think 80% of that is degradation."

If researchers could discover a way to degrade the extra 10% then the virus would enter oblivion, Fishel notes. "We’re pretty sure that access to cDNA is through the ends, which are protected by integrase. If you mutate DNA repair genes so they’re nonfunctional, integration goes up pretty dramatically. In yeast it’s 10 to 1,000 fold; in humans it’s two to five fold."

When these genes are functional they are suppressing integration, and that’s the defense against viruses, Fishel says. These findings suggest possible targets for future HIV drugs, including a host-targeted drug, Fishel notes.

"We want to know all the components of this pathway," Fishel says. "We would like to screen for small molecules which might alter this."

Also, investigators would like to identify other defense pathways and mechanisms, which might be DNA pathways too and which could have been predicted by the yeast research results, Fishel says.

Funding and time are the major obstacles to building on this research and creating a new antiretroviral drug, Fishel says. For example, the development of an integrase inhibitor has taken a considerable amount of time and money, he says.

"Pharmaceutical companies are a little gun-shy about going after something else that’s new," Fishel says. "Instead, they’ll take one mechanism and then vary the drug, as they did with reverse transcriptase inhibitors, as the virus mutates to become resistant."

Nonetheless, the potential of a drug that would use the natural defenses of the DNA repair genes is appealing because this type of drug probably would last far longer, Fishel says.

Essentially, the drug would strengthen HIV’s degradation process by assisting the two DNA repair genes in the destruction of HIV cDNA in cells. This way, there is a reduced pool of HIV cDNA that can integrate into host chromosomes, and this protects cells from infection, Fishel says.

It’s far less likely HIV would be able to develop resistance to this type of host-targeted drug than it does to drugs that target viral proteins, he adds.

"For DNA repair genes, there is no way around degradation," Fishel says. "I think HIV would have to change its whole life cycle in some sense, change the whole picture so it wouldn’t allow access to degradation machinery, and it would be very difficult."

Reference:

  1. Yoder K, et al. The DNA repair genes XPB and XPD defend cells from retroviral infection. Proc Natl Acad Sci USA. 2006;103(12):4622-4627.