Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection

Abstract

Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.

A Single Polymorphism in HIV-1 Subtype C SP1 Is Sufficient To Confer Natural Resistance to the Maturation Inhibitor Bevirimat

“…BVM targets the HIV-1 Gag CA-SP1 boundary region by blocking viral protease cleavage of SP1 from the CA-SP1 precursor and inhibiting release of the mature CA protein, which is the final step required for virion maturation. Despite the novel mechanism of action and initial progress made in small-scale clinical trials (11)(12)(13)17), further development of BVM has encountered unexpected challenges in the clinical setting, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not respond well to BVM treatment (3,10,14,16). These three residues (glutamine-valine-threonine [QVT]) are referred to as the SP1 polymorphism motif.…”

Role of the SP2 Domain and Its Proteolytic Cleavage in HIV-1 Structural Maturation and Infectivity

“…Distinct morphological intermediates have not been detected for wild-type (wt) HIV-1, indicating that maturation is a rapid process. The function of individual cleavage sites has therefore been mainly investigated by introducing mutations that block processing at specific sites or by using the drug bevirimat (31), which selectively inhibits processing between CA and SP1. These studies showed that cleavage sites separating MA and CA, CA and SP1, and SP1 and NC are all essential for viral infectivity (1,24,39,48).…”

Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production

“…For example, in the case of bevirimat, a well-studied HIV-1 maturation inhibitor that blocks the cleavage between CA and p2, even a partial blockage at this cleavage site can elicit a significant antiviral effect (83)(84)(85)(86)(87).…”