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Patterns of resistance development with integrase inhibitors in HIV.

Mbisa JL, Martin SA, Cane PA - Infect Drug Resist (2011)

Bottom Line: More than 30 mutations have been associated with resistance to raltegravir and other IN strand transfer inhibitors (INSTIs).The mutations significantly affect replication capacity of the virus and are often accompanied by other mutations that either improve replication fitness and/or increase resistance to the inhibitors.The recent elucidation of the structure of the prototype foamy virus IN, which is closely related to HIV-1, in complex with INSTIs has greatly enhanced our understanding of the evolution and mechanisms of IN drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Virus Reference Department, Microbiology Services, Health Protection Agency, London, UK.

ABSTRACT
Raltegravir, the only integrase (IN) inhibitor approved for use in HIV therapy, has recently been licensed. Raltegravir inhibits HIV-1 replication by blocking the IN strand transfer reaction. More than 30 mutations have been associated with resistance to raltegravir and other IN strand transfer inhibitors (INSTIs). The majority of the mutations are located in the vicinity of the IN active site within the catalytic core domain which is also the binding pocket for INSTIs. High-level resistance to INSTIs primarily involves three independent mutations at residues Q148, N155, and Y143. The mutations significantly affect replication capacity of the virus and are often accompanied by other mutations that either improve replication fitness and/or increase resistance to the inhibitors. The pattern of development of INSTI resistance mutations has been extensively studied in vitro and in vivo. This has been augmented by cell-based phenotypic studies and investigation of the mechanisms of resistance using biochemical assays. The recent elucidation of the structure of the prototype foamy virus IN, which is closely related to HIV-1, in complex with INSTIs has greatly enhanced our understanding of the evolution and mechanisms of IN drug resistance.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the evolution of raltegravir primary resistance mutations. Initially, mutations conferring resistance to raltegravir have been shown to primarily occur at residues Q148 and N155. Subsequently, switches from 148 or 155 pathways to 148 or 143 pathways have been observed.
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f4-idr-4-065: Schematic representation of the evolution of raltegravir primary resistance mutations. Initially, mutations conferring resistance to raltegravir have been shown to primarily occur at residues Q148 and N155. Subsequently, switches from 148 or 155 pathways to 148 or 143 pathways have been observed.

Mentions: The N155 residue is located on α-helix 4, close to active site acidic residue E152 involved in chelation of metal ions (Figure 3A). The mutation N155H is generally associated with lower raltegravir resistance than Q148 mutations, which may explain its eventual disappearance and replacement with either the Q148R/H/K or Y143C/H/R mutations during raltegravir treatment failure (Figure 4).42,48 This mutant has been shown to reduce the replication capacity of the virus by impairing strand transfer activity and to some extent 3′ processing activity.37,49 A mechanism by which the N155H mutant causes resistance to raltegravir has been reported by Grobler et al. They proposed that the N155 residue in the IN active site interacts with the residues responsible for binding the magnesium cations required for IN activity. As raltegravir binds to IN through interactions with these metal ions, mutation of this residue may prevent raltegravir from binding by disrupting the metal ion active site arrangement.50


Patterns of resistance development with integrase inhibitors in HIV.

Mbisa JL, Martin SA, Cane PA - Infect Drug Resist (2011)

Schematic representation of the evolution of raltegravir primary resistance mutations. Initially, mutations conferring resistance to raltegravir have been shown to primarily occur at residues Q148 and N155. Subsequently, switches from 148 or 155 pathways to 148 or 143 pathways have been observed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108751&req=5

f4-idr-4-065: Schematic representation of the evolution of raltegravir primary resistance mutations. Initially, mutations conferring resistance to raltegravir have been shown to primarily occur at residues Q148 and N155. Subsequently, switches from 148 or 155 pathways to 148 or 143 pathways have been observed.
Mentions: The N155 residue is located on α-helix 4, close to active site acidic residue E152 involved in chelation of metal ions (Figure 3A). The mutation N155H is generally associated with lower raltegravir resistance than Q148 mutations, which may explain its eventual disappearance and replacement with either the Q148R/H/K or Y143C/H/R mutations during raltegravir treatment failure (Figure 4).42,48 This mutant has been shown to reduce the replication capacity of the virus by impairing strand transfer activity and to some extent 3′ processing activity.37,49 A mechanism by which the N155H mutant causes resistance to raltegravir has been reported by Grobler et al. They proposed that the N155 residue in the IN active site interacts with the residues responsible for binding the magnesium cations required for IN activity. As raltegravir binds to IN through interactions with these metal ions, mutation of this residue may prevent raltegravir from binding by disrupting the metal ion active site arrangement.50

Bottom Line: More than 30 mutations have been associated with resistance to raltegravir and other IN strand transfer inhibitors (INSTIs).The mutations significantly affect replication capacity of the virus and are often accompanied by other mutations that either improve replication fitness and/or increase resistance to the inhibitors.The recent elucidation of the structure of the prototype foamy virus IN, which is closely related to HIV-1, in complex with INSTIs has greatly enhanced our understanding of the evolution and mechanisms of IN drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Virus Reference Department, Microbiology Services, Health Protection Agency, London, UK.

ABSTRACT
Raltegravir, the only integrase (IN) inhibitor approved for use in HIV therapy, has recently been licensed. Raltegravir inhibits HIV-1 replication by blocking the IN strand transfer reaction. More than 30 mutations have been associated with resistance to raltegravir and other IN strand transfer inhibitors (INSTIs). The majority of the mutations are located in the vicinity of the IN active site within the catalytic core domain which is also the binding pocket for INSTIs. High-level resistance to INSTIs primarily involves three independent mutations at residues Q148, N155, and Y143. The mutations significantly affect replication capacity of the virus and are often accompanied by other mutations that either improve replication fitness and/or increase resistance to the inhibitors. The pattern of development of INSTI resistance mutations has been extensively studied in vitro and in vivo. This has been augmented by cell-based phenotypic studies and investigation of the mechanisms of resistance using biochemical assays. The recent elucidation of the structure of the prototype foamy virus IN, which is closely related to HIV-1, in complex with INSTIs has greatly enhanced our understanding of the evolution and mechanisms of IN drug resistance.

No MeSH data available.


Related in: MedlinePlus