Introduction - new targets for HIV inhibition

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 patients experienced with all three currently approved classes of antiretrovirals have generally been poor (See Figure 1).

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.

A new approach to the suppression of HIV
Existing classes of licensed antiretrovirals for HIV infection � the reverse transcriptase inhibitors and the protease inhibitors � both act by blocking viral processes that occur inside infected human cells. There is considerable therapeutic potential, however, in stopping the virus getting into these cells in the first place.

This is the aim of a new class of experimental antiretrovirals that target the virus before it enters host cells.

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 an experimental class of anti-HIV drugs known as the fusion inhibitors.

Click here to review a graphical representation of the fusion process