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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

HIV-1 DNA integration. HIV-1 virus synthesizes a dsDNA (red) copy of its RNA genome following entry of the virus into host cell cytoplasm. HIV-1 integrase removes 3′ end GT dinucleotides on both viral DNA ends to expose a 3′ hydroxyl group on terminal adenosines by 3′ processing. The 3′ processed viral DNA is then imported into the nucleus where strand transfer occurs resulting in the integration of the two viral DNA ends into host DNA (black) at positions five base pairs (bp) apart. Host DNA repair enzymes then cleave unpaired viral CA dinucleotides, fill in the five bp gaps (green), and ligate the DNA ends.
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f1-idr-4-065: HIV-1 DNA integration. HIV-1 virus synthesizes a dsDNA (red) copy of its RNA genome following entry of the virus into host cell cytoplasm. HIV-1 integrase removes 3′ end GT dinucleotides on both viral DNA ends to expose a 3′ hydroxyl group on terminal adenosines by 3′ processing. The 3′ processed viral DNA is then imported into the nucleus where strand transfer occurs resulting in the integration of the two viral DNA ends into host DNA (black) at positions five base pairs (bp) apart. Host DNA repair enzymes then cleave unpaired viral CA dinucleotides, fill in the five bp gaps (green), and ligate the DNA ends.

Mentions: Following entry of HIV into a host cell, the virus synthesizes a double-stranded (ds) DNA copy of its RNA genome. The viral DNA is then irreversibly inserted into the host genome in a process called integration.7,8 This is a defining step in the virus life cycle as it establishes a perpetual source of viral progeny for the lifetime of the cell. Integration is mediated by the virally encoded enzyme IN, and targeting this protein or its actions is a useful antiviral strategy.9–13 IN performs two main enzymatic reactions to facilitate the integration of HIV DNA into the host genome. The first reaction, termed 3′ processing, prepares the viral DNA ends for insertion into target DNA by removing a pair of nucleotides at the 3′ end of both viral DNA strands (Figure 1). This exposes a 3′ hydroxyl group on the terminal adenosine of the conserved CA dinucleotide. The 3′ processing occurs in the cytoplasm within a high-molecular-weight preintegration complex (PIC) made up of viral DNA together with viral and cellular proteins.14–18 The 3′ processing step is followed by the active transfer of the PIC into the nucleus, a move facilitated by the interaction of the PIC with nucleopore complex proteins.19


Patterns of resistance development with integrase inhibitors in HIV.

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

HIV-1 DNA integration. HIV-1 virus synthesizes a dsDNA (red) copy of its RNA genome following entry of the virus into host cell cytoplasm. HIV-1 integrase removes 3′ end GT dinucleotides on both viral DNA ends to expose a 3′ hydroxyl group on terminal adenosines by 3′ processing. The 3′ processed viral DNA is then imported into the nucleus where strand transfer occurs resulting in the integration of the two viral DNA ends into host DNA (black) at positions five base pairs (bp) apart. Host DNA repair enzymes then cleave unpaired viral CA dinucleotides, fill in the five bp gaps (green), and ligate the DNA ends.
© Copyright Policy
Related In: Results  -  Collection

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

f1-idr-4-065: HIV-1 DNA integration. HIV-1 virus synthesizes a dsDNA (red) copy of its RNA genome following entry of the virus into host cell cytoplasm. HIV-1 integrase removes 3′ end GT dinucleotides on both viral DNA ends to expose a 3′ hydroxyl group on terminal adenosines by 3′ processing. The 3′ processed viral DNA is then imported into the nucleus where strand transfer occurs resulting in the integration of the two viral DNA ends into host DNA (black) at positions five base pairs (bp) apart. Host DNA repair enzymes then cleave unpaired viral CA dinucleotides, fill in the five bp gaps (green), and ligate the DNA ends.
Mentions: Following entry of HIV into a host cell, the virus synthesizes a double-stranded (ds) DNA copy of its RNA genome. The viral DNA is then irreversibly inserted into the host genome in a process called integration.7,8 This is a defining step in the virus life cycle as it establishes a perpetual source of viral progeny for the lifetime of the cell. Integration is mediated by the virally encoded enzyme IN, and targeting this protein or its actions is a useful antiviral strategy.9–13 IN performs two main enzymatic reactions to facilitate the integration of HIV DNA into the host genome. The first reaction, termed 3′ processing, prepares the viral DNA ends for insertion into target DNA by removing a pair of nucleotides at the 3′ end of both viral DNA strands (Figure 1). This exposes a 3′ hydroxyl group on the terminal adenosine of the conserved CA dinucleotide. The 3′ processing occurs in the cytoplasm within a high-molecular-weight preintegration complex (PIC) made up of viral DNA together with viral and cellular proteins.14–18 The 3′ processing step is followed by the active transfer of the PIC into the nucleus, a move facilitated by the interaction of the PIC with nucleopore complex proteins.19

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