| Introduction to entry inhibitors
Despite the success of highly active antiretroviral therapy (HAART) in extensively reducing the morbidity and mortality associated with HIV infection, new agents are still desperately needed. Many currently available therapies are limited by drug resistance and side effects which restrict the options available for treating the growing numbers of people who have been on long-term therapy utilizing currently licensed antiretrovirals. Furthermore, antiviral responses in triple-class experienced patients have generally been poor (See Figure 1).
Figure 1. Treatment responses in triple-class experienced patients are generally poor
Over recent years there has been a tremendous effort to develop antiretrovirals with new mechanisms of action (activity against new targets) (See Figure 2). Drugs with a completely new mechanism of attacking the virus would be expected to remain active against virus that has already developed resistance to existing classes of antiretrovirals. Drugs with a different mechanism of action may also have non-overlapping or fewer toxicities than existing drugs.
Figure 2: Potential new targets for HIV inhibition
Approaches to the suppression of HIV
The reverse transcriptase inhibitors and protease inhibitors both act by blocking viral processes that occur inside infected human cells. Fusion inhibitors, however, stop the virus getting into these cells in the first place.
HIV entry
It is currently believed that there are essentially three steps through which HIV infects the host cell. This entry process involves a number of HIV and host receptors including the host CD4 and chemokine co-receptors and the HIV envelope glycoproteins, gp41 and gp120 that are collectively called spikes. Each spike is an oligomeric protein (probably a trimer) consisting of 3 subunits of gp120 and three of gp41. The current model of HIV entry can be described by a number of defined steps:
- CD4 receptor attachment� The HIV envelope glycoprotein (gp120) attaches to the CD4 receptor present on the surface of target host cells
- Chemokine co-receptor binding� Conformational changes in gp120 following attachment to CD4 allow gp120 to bind to a chemokine co-receptor found in close proximity to CD4
- Fusion � gp120 undergoes further conformational changes that allows the hydrophobic terminus of gp41 to insert into the host cell membranes bringing the virus and host-cell membranes into contact and allow them to fuse, so enabling the contents of the virion to enter the interior of the host cell.
It is this last step which is targeted by fusion inhibitors.
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