[IN VITRO RESISTANCE TO THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 MATURATION INHIBITOR PA-457]
>>J Virol. 2006 Sep 6; [Epub ahead of print]
IN VITRO RESISTANCE TO THE HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 MATURATION INHIBITOR PA-457 (BEVIRIMAT).
Adamson CS, Ablan SD, Boeras I, Goila-Gaur R, Soheilian F, Nagashima K, Li F, Salzwedel K, Sakalian M, Wild CT, Freed EO.
Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702-1201; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Image Analysis Laboratory, Research Technology Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702-1201; Panacos Pharmaceuticals Inc., 209 Perry Parkway, Gaithersburg, MD 20877; Image Analysis Laboratory, Research Technology Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702-1201.
3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C-terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457, and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single amino acid substitutions that independently confer PA-457 resistance: three at or near the C-terminus of CA (CA-H226Y, L231F, L231M) and three at the 1(st) and 3(rd) residues of SP1 (SP1-A1V, A3T, and A3V). We determined that mutations CA-H226Y, L231F, L231M and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue three mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.<<
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