In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat).

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Abstract Text:

Catherine S Adamson,Sherimay D Ablan,Ioana Boeras,Ritu Goila-Gaur,Ferri Soheilian,Kunio Nagashima,Feng Li,Karl Salzwedel,Michael Sakalian,Carl T Wild,Eric O Freed,

3-O-(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, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-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 3 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.

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Publishing Authors By Initials

CS Adamson,SD Ablan,I Boeras,R Goila-Gaur,F Soheilian,K Nagashima,F Li,K Salzwedel,M Sakalian,CT Wild,EO Freed,

For similar biological phenomena, cell phenomena, and immunity: biological phenomena: microbiologic phenomena: viral physiology: virus replication research abstracts see: biological phenomena, cell phenomena, and immunity: biological phenomena: microbiologic phenomena: viral physiology: virus replication research

PUBMED ID PMID:

MEDLINE DATE:

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of virology

VOLUME: 80

Page Numbers: 10957-71

Journal Abbreviation: J. Virol.

ISSN: 0022-538X

DAY: 6

MONTH: 09

YEAR: 2006

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 113724

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Keywords Mesh Terms:

KEYWORDS: Virus Replication

MESH TERMS: drug effects

Chemical & Substance for Abstract: In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). Information

Substance Name: Viral Proteins

Registry Number: 0

Grant and Affiliation Information for In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat).

AFFILIATION: Virus-Cell Interaction Section, HIV Drug Resistance Program, NCI-Frederick, Bldg. 535/Rm. 108, 1050 Boyles Street, Frederick, MD 21702-1201, USA.

Country: United States

AGENCY: United States NCI

GRANT: N01-CO-12400

ACRONYM: CO

MEDLINETA: J Virol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 Bevirimat Related Publications

• 2D-ELDOR using full S(c-) fitting and absorption lineshapes.
• Acrolein inhibits cytokine gene expression by alkylating cysteine and arginine residues in the NF-kappaB1 DNA binding domain.
• An Alix fragment potently inhibits HIV-1 budding: characterization of binding to retroviral YPXL late domains.
• Beyond Tsg101: the role of Alix in 'ESCRTing' HIV-1.
• Cigarette tar phenols impede T cell cycle progression by inhibiting cyclin-dependent kinases.
• Clinical effect of nemifitide, a novel pentapeptide antidepressant, in the treatment of severely depressed refractory patients.
• Comparative therapeutic effects of dextro and racemic amphetamine sulphate.
• Diagnosis and surgical management of flexor digitorum accessorius longus-induced tarsal tunnel syndrome.
• Dynamic molecular structure and phase diagram of DPPC-cholesterol binary mixtures: a 2D-ELDOR study.
• Effects of regulatory factors on engineered cardiac tissue in vitro.
• Excretion of 3-methoxy-4-hydroxymandelic acid in men with behavior pattern associated with high incidence of coronary artery disease.
• HIV-1 escape from the entry-inhibiting effects of a cholesterol-binding compound via cleavage of gp41 by the viral protease.
• How robust is a neural circuit?
• In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat).
• Influenza virus not cRAFTy enough to dodge viperin.
• Lattice model of equilibrium polymerization. VI. Measures of fluid "complexity" and search for generalized corresponding states.
• Lessons from across the pond: what the US can learn from European immunization programs.
• Measurement of large distances in biomolecules using double-quantum filtered refocused electron spin-echoes.
• Measuring Distances by Pulsed Dipolar ESR Spectroscopy: Spin-Labeled Histidine Kinases.
• Methyl dynamics in proteins from NMR slowly relaxing local structure spin relaxation analysis: A new perspective.
• Microphonic manometer for indirect determination of systolic blood pressure in the rat.
• Minimalist representations and the importance of nearest neighbor effects in protein folding simulations.
• On various uses of the recorded interview in psychotherapy.
• Oxygen effects on the EPR signals from wood charcoals: experimental results and the development of a model.
• Polypeptide motions are dominated by peptide group oscillations resulting from dihedral angle correlations between nearest neighbors.
• Protein dynamics from NMR: the slowly relaxing local structure analysis compared with model-free analysis.
• Solvation effect on conformations of 1,2:dimethoxyethane: Charge-dependent nonlinear response in implicit solvent models.
• Thalamotomy; neuropsychiatric aspects.
• The impact of managed care enrollment on emergency department use among children with special health care needs.
• The role of proteins in the pathogenesis of renal insufficiency.