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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

Structure of the PFV IN active site. A) Structure of PFV IN active site within 14Å of Mn2+ ions showing location of the three active site residues (red sticks), three residues where primary resistance mutations occur (yellow sticks), and Mn2+ ions (green spheres). B) Structure of PFV IN active site in complex with raltegravir showing the three oxygen atoms (red spheres) of the β-hydroxy ketone moiety chelating the Mn2+ ions. The halobenzyl moiety (with brown fluoride atom) is seen stacked close to the cytosine (C) of the CA dinucleotide of the donor DNA strand (purple sticks) which results in the displacement of the terminal adenosine (A) and its 3′ hydroxyl group from the active site. C) Structure of PFV IN active site within 20Å of Mn2+ ions showing location of some of the residues where secondary resistance mutations occur (cyan sticks). PFV residues are indicated, and the corresponding HIV-1 residues are in brackets. The nontransferred DNA strand is shown as brown sticks. Protein data bank codes are 3OY9 and 3L2V,31 and the diagrams were created using RasMol software (University of Massachusetts, Amherst, MA, USA).
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f3-idr-4-065: Structure of the PFV IN active site. A) Structure of PFV IN active site within 14Å of Mn2+ ions showing location of the three active site residues (red sticks), three residues where primary resistance mutations occur (yellow sticks), and Mn2+ ions (green spheres). B) Structure of PFV IN active site in complex with raltegravir showing the three oxygen atoms (red spheres) of the β-hydroxy ketone moiety chelating the Mn2+ ions. The halobenzyl moiety (with brown fluoride atom) is seen stacked close to the cytosine (C) of the CA dinucleotide of the donor DNA strand (purple sticks) which results in the displacement of the terminal adenosine (A) and its 3′ hydroxyl group from the active site. C) Structure of PFV IN active site within 20Å of Mn2+ ions showing location of some of the residues where secondary resistance mutations occur (cyan sticks). PFV residues are indicated, and the corresponding HIV-1 residues are in brackets. The nontransferred DNA strand is shown as brown sticks. Protein data bank codes are 3OY9 and 3L2V,31 and the diagrams were created using RasMol software (University of Massachusetts, Amherst, MA, USA).

Mentions: To date, only one IN inhibitor has been licensed for use in HIV-1 treatment; this being raltegravir which is marketed under the brand name Isentress® (Merck & Co., Inc., White house station, NJ) and was also formerly called MK-0518. Raltegravir, which was approved for use by the US Food and Drug Administration in 2007, is a diketo acid (DKA) analog. A signature feature of DKAs is a β-hydroxy ketone moiety (Figure 2A), and the compounds were the first molecules to be reported as potent and specific IN strand transfer inhibitors (INSTIs). The first two DKA compounds to enter clinical trials were S-1360 and L-870,810, but these agents demonstrated poor efficacy and toxicity, respectively, and were not developed further.32 However, another INSTI, namely elvitegravir, is in the late stages of clinical development and is expected to be approved for clinical use soon, with several others at different stages of development. Elvitegravir is structurally similar to quinolone antibiotics, but like raltegravir, it contains a β-hydroxy ketone moiety (Figure 2B). The crystal structures of PFV in complex with the inhibitors, as well as the structural models of the HIV intasome, show that the oxygen atoms of the β-hydroxy ketone moiety chelate the divalent metal ions that are coordinated by the DDE motif of the IN active site, thereby impeding their participation in the DNA strand transfer reaction (Figure 3A, B). At the same time, the halobenzyl moieties of the inhibitors end stacked up against the cytosine of the CA dinucleotide which forces the reactive 3′ hydroxyl group of the terminal adenosine away from the active site (Figure 3B). The drugs also make contact with residues Q146 and R231.30 In addition, raltegravir interacts with N117, Y143, N144, and P145, while elvitegravir makes only one additional contact with C65.30


Patterns of resistance development with integrase inhibitors in HIV.

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

Structure of the PFV IN active site. A) Structure of PFV IN active site within 14Å of Mn2+ ions showing location of the three active site residues (red sticks), three residues where primary resistance mutations occur (yellow sticks), and Mn2+ ions (green spheres). B) Structure of PFV IN active site in complex with raltegravir showing the three oxygen atoms (red spheres) of the β-hydroxy ketone moiety chelating the Mn2+ ions. The halobenzyl moiety (with brown fluoride atom) is seen stacked close to the cytosine (C) of the CA dinucleotide of the donor DNA strand (purple sticks) which results in the displacement of the terminal adenosine (A) and its 3′ hydroxyl group from the active site. C) Structure of PFV IN active site within 20Å of Mn2+ ions showing location of some of the residues where secondary resistance mutations occur (cyan sticks). PFV residues are indicated, and the corresponding HIV-1 residues are in brackets. The nontransferred DNA strand is shown as brown sticks. Protein data bank codes are 3OY9 and 3L2V,31 and the diagrams were created using RasMol software (University of Massachusetts, Amherst, MA, USA).
© Copyright Policy
Related In: Results  -  Collection

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

f3-idr-4-065: Structure of the PFV IN active site. A) Structure of PFV IN active site within 14Å of Mn2+ ions showing location of the three active site residues (red sticks), three residues where primary resistance mutations occur (yellow sticks), and Mn2+ ions (green spheres). B) Structure of PFV IN active site in complex with raltegravir showing the three oxygen atoms (red spheres) of the β-hydroxy ketone moiety chelating the Mn2+ ions. The halobenzyl moiety (with brown fluoride atom) is seen stacked close to the cytosine (C) of the CA dinucleotide of the donor DNA strand (purple sticks) which results in the displacement of the terminal adenosine (A) and its 3′ hydroxyl group from the active site. C) Structure of PFV IN active site within 20Å of Mn2+ ions showing location of some of the residues where secondary resistance mutations occur (cyan sticks). PFV residues are indicated, and the corresponding HIV-1 residues are in brackets. The nontransferred DNA strand is shown as brown sticks. Protein data bank codes are 3OY9 and 3L2V,31 and the diagrams were created using RasMol software (University of Massachusetts, Amherst, MA, USA).
Mentions: To date, only one IN inhibitor has been licensed for use in HIV-1 treatment; this being raltegravir which is marketed under the brand name Isentress® (Merck & Co., Inc., White house station, NJ) and was also formerly called MK-0518. Raltegravir, which was approved for use by the US Food and Drug Administration in 2007, is a diketo acid (DKA) analog. A signature feature of DKAs is a β-hydroxy ketone moiety (Figure 2A), and the compounds were the first molecules to be reported as potent and specific IN strand transfer inhibitors (INSTIs). The first two DKA compounds to enter clinical trials were S-1360 and L-870,810, but these agents demonstrated poor efficacy and toxicity, respectively, and were not developed further.32 However, another INSTI, namely elvitegravir, is in the late stages of clinical development and is expected to be approved for clinical use soon, with several others at different stages of development. Elvitegravir is structurally similar to quinolone antibiotics, but like raltegravir, it contains a β-hydroxy ketone moiety (Figure 2B). The crystal structures of PFV in complex with the inhibitors, as well as the structural models of the HIV intasome, show that the oxygen atoms of the β-hydroxy ketone moiety chelate the divalent metal ions that are coordinated by the DDE motif of the IN active site, thereby impeding their participation in the DNA strand transfer reaction (Figure 3A, B). At the same time, the halobenzyl moieties of the inhibitors end stacked up against the cytosine of the CA dinucleotide which forces the reactive 3′ hydroxyl group of the terminal adenosine away from the active site (Figure 3B). The drugs also make contact with residues Q146 and R231.30 In addition, raltegravir interacts with N117, Y143, N144, and P145, while elvitegravir makes only one additional contact with C65.30

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