|How HIV fuses to a cell|
One new class of drug is a subset of the class called entry inhibitors. The drug enfuvirtide (T-20) is one subset of entry inhibitors known as fusion inhibitors. A fusion inhibitor blocks the activity of HIV where the virus sends out a projectile, said to resemble an extremely small harpoon that anchors the virus to a CD4 T cell. The virus pulls itself in via this anchor until it makes direct contact with the cell. Once full contact is made, the virus inserts its genetic material into the cell (Steps 1-4).
Another subset of entry inhibitors, known as a receptor blocker (A), is conceptually similar to but distinct from, fusion inhibitors. Receptor blockers work one step before fusion inhibitors (B). Before a virus can "shoot its harpoon" and fuse with the cell, it must first find and "dock" with the appropriate cell. This step brings the virus close enough for the "harpoon" of the fusion step to be fired. It does this by producing proteins that interlock with other proteins (called receptors) on the cell's surface. The virus will ignore cells that lack the necessary receptors.
|A. Receptor Blocker|
|B. Fusion Inhibitor|
For many years, researchers knew that HIV used a receptor called CD4 to find and link up with the cells it infected, though lab data long suggested that the CD4 receptor alone did not explain all aspects of the virus/cell interaction. In mid-1996, Robert Gallo and co-workers published a key finding that showed how HIV could be suppressed by a number of naturally occurring immune chemicals known as chemokines. Within months, other researchers, most notably Edward Berger and co-workers at the National Institutes of Health, demonstrated that these chemicals affected the virus' activity because there were receptors for them on the cells that became infected by HIV. The presence of the chemicals blocked HIV's ability to interact with those receptors and infect the cell. The first identified of these "co-receptors" is called CCXR5. A second co-receptor, CXCR4 (also called fusin), was soon identified and associated with a form of HIV that is considered to be more destructive of T cells and is usually seen only in advanced or rapidly progressive disease. Other co-receptors have since been identified, including CCR7, though their importance is less understood. Most of the connection activity between HIV and infected cells, however, was explained by the CD4, CCXR5 and CXCR4 receptor interactions. (For more information about HIV Co-Receptors, call the Project Inform hotline.) It stood to reason that blocking the most common receptors would help slow the activity of HIV and a race was on to find drugs that would block them. That search has now begun to bear fruit.
These drugs all work by preventing entry of the virus into the cell, but they do it by different mechanisms.
The entry inhibitor/receptor blocker farthest along in studies is SCH-C, or Schering C from Schering Plough. SCH-C works by blocking the CCXR5 receptor. The drug is currently in a phase 1 dose-ranging study that is using it as single agent therapy (monotherapy) for 10 days. The study is underway in France and the US. Although the study is uncontrolled (i.e., no one received a placebo or other drug for comparison) and results to date are from a small number of volunteers, it is clear that the drug has a significant anti-HIV effect, even at very small doses.
Testing SCH-C has been a long, slow process, largely because of a potential side effect that might affect a particular heart rhythm called the QT time. QT times were altered in some HIV-negative volunteers who used the highest dose of the drug (600 mg) in the first round of studies. This effect was also observed earlier in animal studies. Because of this, the Food and Drug Administration (FDA) has required that all volunteers in these early studies have their heart rhythms continually monitored while on the drug. This requires that volunteers be hospitalized and connected to monitoring devices throughout the 10-day duration of the study. It is a fairly demanding study and has been hard to find volunteers. Those who volunteer under these circumstances are making an important contribution to the development of future drugs for HIV.
To date, the studies have shown only small changes in QT times (the side effect the FDA is concerned with) that do not seem related to the dose of the drug. Researchers, however, point out that the variations seen in QT time are small and not of the size that would be considered harmful. They also note that it is has been difficult to know whether these small changes mean anything at all, since there is no standard to compare them to. No one has measured QT times continuously for ten days to determine how much variation is normal, either in HIV-positive or negative people. It may be that small variations over time are the norm. The people who showed the most significant "events" (three or more irregular heartbeats in a row) were unaware that anything had happened, and there were no other consequences. Moreover, it is known that QT times are different in men and women, further complicating analysis. Finally, it is unclear whether the effects seen in a short 10-day study are predictive of what will be seen in people who take the drug continually. For now, it is reasonable to say that no significant problems have yet been seen. The most recent round of the studies now includes a "placebo" group (people who are continuously monitored while in a hospital setting but who did not receive the drug). This may help determine what is "normal."
Schering has a second CCXR5 inhibitor in development, currently known as SCH-D. In lab studies SCH-D appears to be more potent than SCH-C and has so far not been shown to affect QT times. Studies in HIV-positive people, however, are just beginning so it impossible to predict whether SCH-C or SCH-D will prove more beneficial overall.
Pfizer Labs also has a promising CCXR5 inhibitor in the earliest stages of human testing but no data are yet available on this compound. A number of other companies are said to be working on entry inhibitors, but no others have yet begun human studies.
Bristol Myers has an entry inhibitor that blocks the other common receptor, CD4. Human studies of this compound have already begun, but the company has as yet provided no information, even about the design of the study. Combining a CCXR5 inhibitor with a CD4 inhibitor would seem to offer great hope. Best-case scenario for the Schering C drug might lead to wide availability, if warranted, approximately two years from now.
One concern raised about CCXR5 entry inhibitors is whether suppressing or blocking the CCXR5 receptor might cause HIV to change to the form that uses the other receptor called CXCR4. Versions of HIV which use CXCR4, at least when they occur naturally, tend to be more aggressive and harmful than those that use CCXR5 -- though this is somewhat controversial. If this switch occurs, some feel it might negate the value of CCXR5 entry inhibitors and produce a worse outcome. At least one published laboratory study, however, seems to show that this does not happen. Other scientists believe that blocking the CCXR5 receptor will have no bearing on whether the virus does or doesn't try to use the CXCR4 receptor. Time and more studies will answer this question.