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The Best Offense?

The Best Offense? CCR5 inhibitors, moving toward market, suggest it may be a good defense By Simon Frantz Related Articles 5 HIV Treatment Strategies A piggyback attack: Using the common cold to deliver an HIV vaccine Stem cells and gene therapy: Researchers take a second look at using stem cells to treat HIV Solving the viral spike: Can structural biology find a chink in HIV's armor? Reconstructing early HIV: The search for immunogen

Simon Frantz

The Best Offense?

CCR5 inhibitors, moving toward market, suggest it may be a good defense

By Simon Frantz

All oral HIV drugs work by fighting the virus once it has entered human immune cells. Soon, however, defense could be a new form of attack. A CCR5 inhibitor called maraviroc is close to being the first oral treatment for HIV patients that prevents the virus entering uninfected host...

In the early 1990s the concept of creating HIV drugs that target host immune cells began unsuccessfully with attempts to block the CD4 receptor. It was only when researchers discovered that the chemokine CCR5 receptor is the main coreceptor that most HIV strains use with CD4 to enter human cells, (Science, 276:51-2, 1997) that people began to believe that this approach was possible.

Drug developers were excited about the CCR5 receptor because it belongs to a family of proteins known as G-protein-coupled receptors (GPCRs), known to be excellent therapeutic targets for many conditions. Also, studies showed that people who lacked CCR5 receptors because of a naturally occurring genetic mutation called D32 rarely contracted HIV, and appeared to have well-functioning immune systems and a normal life expectancy (J Am Med Assoc, 296:815-26, 2006).

"When these studies were published, everyone took a close look at CCR5," says Manos Perros, director and head of anti-infectives biology at Pfizer, the company developing maraviroc. "Here was a new target we thought could be druggable, and we effectively had clinical validation by a naturally occurring mutation indicating the target could work and be safe."

From the start, creating a CCR5 inhibitor wasn't easy. Perros' team made many compounds that blocked the receptor, but none of them had any antiviral activity. "We asked ourselves if we were working on the right target, and whether the original data were actually meaningful," says Perros.

It turns out that small molecules can bind to CCR5 in many ways, but only a few can block HIV binding, too. "We did not have a very clear understanding of the interaction between the virus and the host target," says Perros. "This is the challenge that any team faces when working on host targets."

After months of looking at binding properties of CCR5 mutants, molecular modeling to see how compounds bind to the receptor, and trial-and-error biology, Perros' team finally had its eureka moment. "I still remember the day my colleague came to me saying that we finally had an antiviral compound, though I can't say that the nine months leading up to that day were as enjoyable," says Perros.

The challenges didn't end there. Other CCR5 inhibitors in development at the same time failed in clinical trials. GlaxoSmithKline stopped development of aplaviroc in September 2005 when some drug-naive patients developed liver damage. Soon after, Schering-Plough halted clinical trials of vicriviroc after it found that combination therapy with the drug was inferior to combination therapy without the drug.

Pfizer's maraviroc, on the other hand, seemed to be effective. Patients taking maraviroc, with an optimized background regimen, had an increase in CD4 cells nearly twice that seen in those receiving optimized regimen alone, and around twice as many patients on maraviroc had undetectable virus in the blood.

However, maraviroc hit a roadblock in June of this year when the US Food & Drug Administration delayed its approval, despite an advisory committee recommending that the drug be approved. Maraviroc was eventually granted accelerated approval in August and will be known as Selzentry, but Pfizer has to provide long-term study data for the FDA to grant the drug full approval. In July, the scientific committee of the European Medicines Agency also recommended approval of the drug.

As with all other HIV drugs, resistance is an issue. Already, researchers have found two resistance mechanisms in vitro that are being further investigated in patients.Already researchers have found that the virus can switch to a related coreceptor called CXCR4 to enter cells. This so-called X4 variant of the virus is more virulent in vitro, yet somehow it is rarely seen in humans until later in the disease course. "The question of what keeps X4 variants from replicating in vivo is a fascinating one, and one that has no answer that I'm aware of," says Michael Lederman, director of the Case Western Reserve University/University Hospitals of Cleveland Center for AIDS Research in Ohio.

The virus can also change its structure to bind to the receptor even when the CCR5 inhibitor is attached (Virology, 361:212-28, 2007). "This shows, if we needed reminding," says Lederman, "that the virus is very flexible and capable of doing anything and everything it needs to do to survive."

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