February 2001: Grants Seek to Identify New Anti-HIV Drug Targets
In February 2001, the American Foundation for AIDS Research awarded 13 basic research grants totaling $1,168,431 for projects to help speed the discovery and development of new anti-HIV drugs. The funded projects are studying HIV genes and gene products, as well as specific components of human cells that are essential to HIV’s ability to infect cells and replicate. The hope is that a better understanding of these viral and cellular components will allow researchers to design new drugs that can interfere with their function, and thus prevent HIV from reproducing. This should reduce viral load and slow disease progression in HIV-infected individuals.
Highly active antiretroviral therapy (HAART) has never worked for some people with HIV/AIDS, and many more cannot tolerate its debilitating side effects. Even among those who do well on HAART, roughly half begin to experience treatment failure after a year or two, often because HIV has developed resistance to the drugs currently used to inhibit its growth. And once HIV develops resistance to a single medication, it becomes progressively easier for the virus to develop resistance to other drugs or even an entire class of HIV drugs. According to a study released at the 8th Conference on Retroviruses and Opportunistic Infections, as many as 14% of people newly infected with HIV in the U.S. are acquiring strains of the virus that are already resistant to one or more of the current antiretroviral drugs.
Most researchers in both the pharmaceutical industry and academia have responded to the need for new anti-HIV drugs by creating different versions of existing medications, which attack HIV’s reverse transcriptase or protease enzymes in an effort to block viral reproduction. The reasons for this are threefold. First, these classes of drugs have a track record, so some success is virtually guaranteed. Second, the laboratory tests needed to measure the effects of such drugs already exist. And third, the pharmaceutical industry recognizes the therapeutic potential that these types of drugs have for other diseases. For example, protease inhibitors are now being developed for use against hepatitis and herpes viruses, and a protease inhibitor against the common cold virus is already in human trials.
There has been only one significant breakthrough in HIV/AIDS treatment since the advent of protease inhibitors in early 1996. As reported in several scientific journals and in the January 15, 2001, issue of Time magazine, a number of researchers are now exploring a new class of anti-HIV drugs called “entry” or “fusion” inhibitors, which would block HIV from binding to and infecting healthy cells. Several amfAR-funded researchers had a key role in identifying the targets for these inhibitors, notably Drs. Nathaniel Landau, now of The Salk Institute, and Daniel Littman of New York University. Progress on this new class of drugs is encouraging. But additional basic research and rigorous clinical testing will be required before entry and fusion inhibitors can be brought to market, and it is likely that HIV would eventually develop mutated strains that are resistant to them. There is a critical need for alternative methods of stopping or slowing the HIV disease process.
Accordingly, amfAR’s latest targeted research initiative takes an entirely new approach, focusing on (1) “accessory” genes and gene products of HIV that have been previously neglected in drug development; (2) cellular proteins that HIV needs in order to reproduce but that may not be essential to human cell function; and (3) the development of new laboratory tests to assess the activity of chemical compounds against these new targets.
A high degree of pent-up demand for funds to support research in these areas was evidenced by the fact that amfAR received more letters of intent (129) in response to the request for proposals for this initiative than in any previous targeted grant cycle. Forty-one grantees were invited to submit full proposals, and one-year grants of approximately $90,000 each have been awarded to 13 researchers affiliated with major universities and research centers nationwide. As always, grantees were selected through stringent peer review by qualified members of amfAR’s Scientific Advisory Committee, a team of physicians and scientists who volunteer their time and expertise to evaluate research proposals on the basis of their scientific merit, promise, and relevance.
Several of the new grantees are focusing on HIV proteins and genes, with the intent of identifying new viral targets for new drugs. For example, one of the funded proposals is looking at ways to disrupt the function of HIV’s nucleocapsid (NC) protein, which helps the genetic material of HIV to enter the nucleus of infected cells, where the viral genetic material is duplicated to make more virus.
Other grant recipients are focusing on the components of healthy human cells that HIV must co-opt for its own growth. In tandem with these grant awards, amfAR hopes to speed the development of screening tests that will be needed to evaluate the activity of compounds against new viral and cellular targets, preferably tests capable of handling very large numbers of compounds, known as “high throughput assays.”
The Foundation also seeks to take a more proactive, hands-on approach to accelerating the pace of research already underway in this area. Where effective laboratory or in vitro tests already exist, scientists need access to large collections or libraries of chemical compounds to screen for possible activity against potential viral and cellular targets. amfAR will license the use of these resources, known as “combinatorial libraries,” from biotech companies for screening purposes. Any compound or molecule that shows activity in a screening test will be considered a “lead compound” for further development as a potential drug against the target.