International AIDS Society Conference Update

Compound targeting Rev protein promising

Orphaned approach still looking for home

While clinicians and HIV/AIDS patients anxiously watch the trend of the virus developing resistance to multiple antiretroviral therapies, the question remains whether new drug research will continue to save the day.

Some suggest there will need to be multiple new classes of antiretroviral drugs developed to stretch further the life span of longtime HIV patients.

One potential new class would target the Rev protein, an approach that has received very little attention from the research and pharmaceutical communities.

"We’ve been very frustrated by the apparent lack of interest among big pharma and the research community in general," says David Rekosh, PhD, a professor of microbiology in the department of microbiology at the University of Virginia in Charlottesville. He also is the director of the university’s Myles H. Thaler Center for AIDS and Human Retroviruses Research.

Rekosh and his wife and co-investigator Marie-Louise Hammarskjöld, MD, PhD, a professor of microbiology at the University of Virginia and associate director of the Thaler Center, have been working on Rev as a potential drug target for 20 years with the help of NIH funding, he reports.

"The real importance of this work is that it points to a drug target that has been broadly overlooked," Rekosh says.

A study the pair presented at the International AIDS Society’s Third Conference on HIV Pathogenesis and Treatment, held July 24-27, 2005, in Rio de Janeiro, Brazil, demonstrates that a compound targeting the Rev protein can inhibit viral replication.1

"Rev works by binding to the site on viral RNA, and that RNA, together with Rev, gets transported from the nucleus to cytoplasm," Rekosh explains.

When Rev is missing, genomic RNA cannot leave the nucleus, so the Rev protein is essential for HIV replication. A drug that inhibits the Rev protein would essentially stop HIV dead in its tracks, he adds.

"So Rev really is an excellent drug target because the interaction between Rev and RNA is completely virus-specific in nature," Rekosh says. "There are no cellular proteins that are essential for that reaction to take place."

As such, when an agent inhibits Rev from binding to RNA, it only interferes with functions that are viral specific, he adds.

Since the approach is novel, there should be no viral resistance initially, and this makes it another weapon to add to the current arsenal, which may one day be obsolete.

The problem is that compounds are years away from clinical trials, partly because the researchers who have discovered the approach are in need of the type of resources and collaboration that only the for-profit drug industry can provide, including work with organic chemists, Hammarskjöld reports.

"Right now, the compounds aren’t potent enough to expect them to work in animals or people, but this is the way almost any compound that’s newly discovered starts off," Rekosh says. "In order for it to be effective as a drug, we are going to have to make the compounds work better by doing chemical modifications to them."

While pharmaceutical manufacturers primarily have focused on enzyme inhibition, there is no reason they couldn’t go after Rev inhibitors now that there has been some success with targeting large molecules like the entry inhibitors do, he notes.

"There’s a little more acceptance of the notion that this would be a good target," Rekosh reports.

"There’s been general skepticism in the pharmaceutical industry to being able to inhibit protein-protein and protein-RNA interactions using small chemical molecules," Hammarskjöld says. "Our belief in the case of Rev is that this may be due to the fact that efforts that have been made in the past by drug companies have focused on screening methods measuring in vitro interactions, and ours is an intracellular assay."

The research demonstrates that the compounds discovered by the Thaler Center research team almost certainly target Rev and prevent the virus from replicating within a cell culture, so it may be possible to develop these into drugs, Rekosh says.

Although a Rev inhibitor has the potential to be very effective in stopping HIV replication, it wouldn’t be a panacea, as HIV eventually would likely develop resistance to it just as the virus has to protease inhibitors and other antiretrovirals, Rekosh notes.

"Just by chance there would likely be a mutated version of Rev or the RNA sequence to which Rev binds that can no longer interact with the compound or which interacts with the compound less well," he explains.

The Rev inhibitor research began with a partnership with a biotech company that has since gone out of business, Rekosh says.

He estimates it will cost at least several tens of millions of dollars to take the Rev inhibitor compound through the research necessary to bring a drug to market; that’s why it will be necessary for the investigators to find a pharmaceutical industry suitor to complete the work.

"So this is the beginning of a long road," Rekosh says. "We really think Rev needs to be taken more seriously by people looking for better HIV drugs, and it is our goal to make this happen."

Reference

  1. Rekosh D, et al. Novel compounds that inhibit HIV replication by acting through inhibition of HIV rev function. Poster presented at the International AIDS Society’s Third Conference on HIV Pathogenesis and Treatment. Poster WePp0106. Rio de Janeiro, Brazil; July 2005.