Weill Cornell Scientists Help Identify "Promising" New Drug for HIV Infection
Reveal How HIV Escapes an Inhibitor<br /><br />Articles Report Results with Antagonists of an HIV Receptor, CCR5
Jan 15, 2002
Two recent papers in Proceedings of the National Academy of Sciences—with Professor John P. Moore of the Department of Microbiology and Immunology at Weill Cornell Medical College as the senior author or a co-author—trace promising channels to pursue in the molecular biology of the fight against infection with the AIDS virus, HIV. One paper, in the October 23 issue, identifies a compound, SCH-C, that is a potent inhibitor of HIV infection. The other paper, in the January 8 issue, reveals how, in replicating itself in blood cells, HIV "escapes" compounds like SCH-C that inhibit its entry into cells via an important receptor called CCR5.
The two papers appear after a decade of experience with the HIV drugs known as protease inhibitors and reverse transcriptase inhibitors. Although these drugs have helped many patients, the virus's resistance, coupled with the difficulty of following the prescribed daily regimen, has meant a continuing need for still more effective drugs; hence the importance of the first paper. Besides, the virus has a proven ability to mutate and escape from virtually any drug, so the second paper's explanation of how it does this in the laboratory is also important.
Both papers focus on the pathway by which HIV (or HIV-1, the common type of the virus studied here) can use the CCR5 receptor to enter blood cells. Because of its nature, the CCR5 receptor is an especially promising target for pharmacologic intervention. It is the receptor used by the most commonly transmitted HIV strains, especially early in the infection. And an antagonist that is specific for CCR5 is likely to cause few side effects.
The first set of authors, led by Bahige M. Baroudy and Julie M. Strizki of Schering-Plough Research Institute, New Jersey, describe SCH-C as "a small molecule antagonist that is specific for CCR5 and displays potent antiviral activity against HIV-1 strains from multiple genetic subtypes in vitro. Moreover, SCH-C strongly inhibits HIV-1 replication" in a mouse model "and has excellent pharmacological properties in rats and primates." In addition, "preliminary data from our laboratories and others ... indicate that SCH-C acts synergistically with other antiretroviral agents in vitro, suggesting that inhibitors of viral entry could be used in conjunction with existing therapies to suppress HIV-1 replication."
SCH-C is readily absorbed by the body when taken by mouth. It is now being tested for safety and antiviral effect in phase 1 human trials.
The second set of authors—led by Alexandra Trkola, who is now at the Division of Infectious Diseases, Department of Medicine, University Hospital, Zurich, and Shawn E. Kuhmann of Weill Cornell Medical College—set out to determine how HIV-1 would escape from a CCR5-specific small molecule inhibitor (as it inevitably would) and whether it would do so by using a receptor called CXCR4. As the authors explain, "there are concerns that blocking CCR5 with a specific inhibitor in vivo might force HIV-1 to evolve to use CXCR4 instead." That would place limits on a CCR5-specific antiviral strategy.
In their study, the authors "passaged" the virus many times in blood cells (specifically, peripheral blood mononuclear cells) with increasing concentrations of the CCR5-specific small molecule inhibitor AD101 (a compound related to SCH-C). "By 19 passages, an escape mutant emerged with a greater-than-20,000-fold resistance to AD101," the authors report. However, the virus does not do this by using CXCR4. "Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor."
The authors conclude by arguing that suppression of the virus through CCR5-specific inhibitors in vivo would not necessarily lead to mutant viruses that use CXCR4. "Whether the evolution of HIV-1 to use CCR5 with a higher affinity, or in a different way, might have adverse consequences in vivo needs to be considered, but the present study argues against the notion that coreceptor switching to CXCR4 use must necessarily be a rapid consequence of the use of CCR5 inhibitors in HIV-1-infected people."
Besides Drs. Strizki, Baroudy, and Moore, the first paper has 22 other authors. Dr. Moore's Department had the support of the William Randolph Hearst Foundation, and his laboratory received a grant from the National Institutes of Health. Dr. Moore is a Stavros S. Niarchos Scholar in the Department of Microbiology and Immunology at Weill Cornell.
Besides Dr. Trkola, Kuhmann, and Moore, there were 14 other authors of the second paper, including, from Weill Cornell, Tom Ketas, Tom Morgan, and Pavel Pugach. This work was also funded by the NIH.
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