Combining entry inhibitors: new avenue for therapy

Keith Alcorn
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This article is more than 24 years old.

A combination of three drugs which block the entry of HIV into cells at different sites may be a new avenue for HIV therapy, and one of particular value for people with extensive experience of all the currently available drugs. The first study to look at the value of combining drugs which block HIV entry into cells was presented yesterday at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto.

The drugs used in the study were:

  • T-20, a fusion inhibitor being developed by Trimeris in collaboration with Roche. T-20 blocks fusion of HIV by binding onto HIV’s gp41 protein, an essential docking mechanism for viral entry into host cells.

  • PRO 542, an entry inhibitor being developed by Progenics Pharmaceuticals. PRO 542 mimics the CD4 receptor on T-lymphocytes, and interferes with viral attachment to CD4 cells.

  • PRO 140, a co-receptor inhibitor, also being developed by Progenics. PRO 140 mimics the CCR5 co-receptor on the surface of CD4 cells that is also used by HIV to gain entry to CD4 cells.

Glossary

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.

entry inhibitors

A group of antiretroviral medications that block HIV from entering a host CD4 cell. Includes both CCR5 inhibitors and fusion inhibitors.

synergy

When two or more drugs produce an effect greater than adding their separate effects.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

The Progenics research group tested the effects of the agents individually and in combination against test tube samples of HIV to see whether the drugs could boost each other’s effects (synergy). T-20 and PRO 542 were found to be synergistic, to such an extent that when used together, concentrations of the drugs required to inhibit HIV replication could be reduced 30-fold in comparison with the concentrations required when used individually. PRO 140 was not synergistic, but in a separate test tube study, it was shown to be a potent inhibitor of HIV activity not only in lymphocytes, but also in macrophages, an important reservoir of HIV infection.

PRO 542 and T-20 are both advanced in human studies, but PRO 140 hasn’t been tested in humans yet. T-20 is likely to be the first drug targeted at HIV entry to be licensed, possibly as early as late 2001, and these findings make it all the more urgent to define the possibilities of combining entry inhibitors so that the potential of T-20 is not squandered.

References

Olson W et al. Potent, synergistic inhibition of HIV-1 by combinations of the viral entry inhibitors PRO-542 and T-20. 40th ICAAC, Toronto, abstract 549, 2000.

Olson W et al. Potent, broad-spectrum inhibition of HIV-1 by the CCR5 antibody PRO 140. 40th ICAAC, Toronto, abstract 550, 2000.

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