A new mechanism by which drugs block HIV-1 from entering host cells, has been discovered by scientists.
Cellular invasion by HIV-1 requires the concerted action of two proteins on the viral surface: gp120 and gp41. The function of gp41 is to get the viral contents into the interior of the host cells.
AdvertisementThis requires the association of two distinct regions of gp41 called N-HR and C-HR. Anti-HIV-1 agents known as fusion inhibitors target the N-HR or C-HR and disrupt their association, which prevents the virus from entering into the host cell. One drug that works like this is Fuzeon (Roche), and there are other agents in the pipeline.
However, blocking the N-HR/C-HR association is not the only mechanism by which fusion inhibitors prevent HIV-1 entry, say scientists from the Kimmel Cancer Center at Jefferson. The inhibitors also induce irreversible deactivation of gp41.
"After these drugs bind, they seem to shuttle gp41 into a dead conformation from which the protein cannot recover. Importantly, the speed of this drug-induced deactivation greatly influences how potent a drug is at preventing HIV-1 infection," said Michael Root, assistant professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University.
When the inhibitors bind to the gp41 C-HR, the protein rapidly deactivates before inhibitors have time to dissociate. But when the inhibitors bind to the gp41 N-HR, deactivation takes a very long time, and many inhibitors can readily unbind.
To potently inhibit HIV-1 entry, a C-HR targeting fusion inhibitor can have a relatively low affinity, but an N-HR targeting fusion inhibitor must bind extremely tightly.
A major disadvantage of using Fuzeon and related drugs that target N-HR is the rapid emergence of HIV-1 strains resistant to the drugs.
The new study suggests that the resistance phenomenon is related to the slow speed of gp41 deactivation induced by these fusion inhibitors.
HIV-1 appears to have more difficulty developing resistance to drugs that can remain bound to gp41 for much longer than gp41 takes to deactivate, even if the drugs are no more potent than Fuzeon against the original HIV-1 strain.
Armed with this knowledge, the researchers have developed a new strategy to improve the antiviral activities of N-HR-targeting fusion inhibitors.
The study has been published in PLoS Pathogens.