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Coverage provided by Calvin J. Cohen, M.D., M.S.

July 10, 2001

• The Next Target in Therapy: Viral Entry (Abstract PL9)
  Speaker: E. Hunter
  Authored by Hunter, E.; UAB Center for AIDS Research, University of Alabama, Birmingham, AL, USA

In order for HIV to do damage to our cells, it must first attach onto our cells. After attachment, it must fuse with our cells. This fusion allows HIV to inject its RNA into our cells, and this RNA then starts a process of transcription, integrating itself into our cellular DNA. However, if there were ways to block HIV from fusing with our cells, HIV would not do us harm, since if HIV cannot get into our cells, it is likely to die off within a day or so. Therefore, there has been significant research in recent years to find drugs that may prevent viral entry in to our cells.

Dr. Hunter reviewed the steps that HIV takes to enter our cells. The first step is the attachment of HIV to our cell, mainly through the interaction of a viral protein called gp120 and one cell surface protein called CD4. This interaction starts the process of viral attachment. After this attachment, the virus then lines up with a second receptor on our cells, called the co-receptor. There are two common ones that are involved here: one called CXCR4, and the other called CCR5. After co-receptor attachment, HIV lines up its proteins and, using a harpoon type protein, it injects a protein into our cell membrane. After this occurs, HIV then pulls itself closer to the cell membrane, and fuses its membrane with our cell membrane in a process that is still incompletely understood. Each of these steps, however, provides an opportunity for a drug to block viral entry.

For example, over the years, there have been several drugs designed to interfere with the binding of viral gp120 to the cellular CD4 receptor. While several approaches in the past were not successful, there is a more recent medication in development that appears to be active at this step. This agent, manufactured by ProGenics, and called Pro 542, has been tested in small studies, and shows about a half-log drop at the doses tested so far. Further work is expected on this and other agents that are active at this step.

There are several agents in development which target the co-receptor interaction. One approach has been to block CCR5 in particular, since it was also noted a few years ago that people who do not have this CCR5 receptor appear to be quite healthy as well as resistant to HIV infection. (Unfortunately about 1% or so of humans have this genetic difference.) The drug company Schering has had a few products tested that block CCR5 and these are undergoing active investigation. Other companies are exploring CXCR4 inhibitors, although one called AMD 3100 has stopped development, as there was minimal activity at the doses tested.

Fusion inhibitors have been the most successful of the entry inhibitors to date. These drugs block the step after co-receptor binding, and interfere with the process that HIV uses to pull itself towards the cell membrane. Furthest along is a drug called T-20. As a single drug, it has shown that it is quite potent as an antiviral, in the range of many of the more potent antivirals currently in use. While it is given by subcutaneous self injection twice a day (similar to insulin), studies reported here of those who have done this for a year report that the vast majority of study participants find that it is very manageable, noting minimal interference in daily life with regard to side effects. These results are heartening given that these agents are currently unlikely to be available in pill form. Furthermore, there are already "second generation" fusion inhibitors in study. One is called T-1249, also being developed by Trimeris in collaboration with Roche. Reports earlier this year confirm that T-1249 is also active against HIV, and appears to be active against HIV that has become resistant to T-20.

It appears hopeful that a more precise understanding of the key steps required by HIV to attach onto cells and then fuse with it, will continue to lead to an increased number of antiviral agents, each with enormous potential to act effectively to halt the damage done by HIV infection.

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