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Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection.

Katlama C, Murphy R - Ther Clin Risk Manag (2009)

Bottom Line: Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development.Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed.The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

View Article: PubMed Central - PubMed

Affiliation: Pierre et Marie Curie Université - Paris 6, Service de Maladies Infectieuses et Tropicales, Paris, France.

ABSTRACT
Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development. Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed. Two drugs in this class have reached late stages of development for use in HIV-1 infected individuals: raltegravir, which has just been approved for use in treatment-experienced patients, and elvitegravir, currently in phase III trials. Both are potent with an IC(50) in the 30 nM range and active in vitro against wild type as well as in strains highly resistant to all other existing classes of drugs. Clinical trials in both treatment-naïve and -experienced patients have demonstrated raltegravir to be highly effective with an excellent tolerability profile and no specific clinical or metabolic side effects. Longer follow up is necessary to ensure this early safety profile is sustained. The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

No MeSH data available.


Related in: MedlinePlus

Integrase: mechanism of action for integrase inhibition. Modified from Hazuda DJ. 2006. Inhibitors of human immunodeficiency virus type I integration. Curr Opin HIV AIDS. 1:212–217.36Abbreviations: PIC, preintegration complex; LTRs, long terminal repeats.
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f2-tcrm-5-331: Integrase: mechanism of action for integrase inhibition. Modified from Hazuda DJ. 2006. Inhibitors of human immunodeficiency virus type I integration. Curr Opin HIV AIDS. 1:212–217.36Abbreviations: PIC, preintegration complex; LTRs, long terminal repeats.

Mentions: Integrase is an HIV-1 enzyme that is essential for viral replication. Integrase catalyzes at least 3 reactions: 3′ processing, formation of the preintegrase complex, and strand transfer (Figure 2). Briefly, once the viral RNA is retrotranscribed into DNA by reverse transcriptase, integrase removes a 3’ terminal portion at both ends of the newly formed DNA where it remains bound, stabilizing the preintegrase complex. Once 3’ processing occurs, the preintegrase complex can form which consists of ring-shaped viral DNA with associated virus and host proteins. This complex structure is able to translocate across the nuclear membrane and into the nucleus. The final reaction catalyzed by integrase is the strand transfer where both 3’ ends of the DNA are inserted into the host DNA or chromosome. The newly altered host DNA, which now includes the HIV DNA, requires repair which is done with cellular DNA repair enzymes. If strand transfer in inhibited, the viral ring structures remain in the nuclear cytoplasm, the clinical relevance of which is unknown.11–12 Inhibitors of integrase that have now been developed are strand transfer inhibitors (INSTIs) that block the insertion position on the host DNA. Three integrase inhibitor classes of compounds have been identified: diketoacids, hydroxyquinolones, and polyphenols. Raltegravir is a member of the diketoacid class and elvitegravir belongs to the hydroxyquinolone class.14


Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection.

Katlama C, Murphy R - Ther Clin Risk Manag (2009)

Integrase: mechanism of action for integrase inhibition. Modified from Hazuda DJ. 2006. Inhibitors of human immunodeficiency virus type I integration. Curr Opin HIV AIDS. 1:212–217.36Abbreviations: PIC, preintegration complex; LTRs, long terminal repeats.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697544&req=5

f2-tcrm-5-331: Integrase: mechanism of action for integrase inhibition. Modified from Hazuda DJ. 2006. Inhibitors of human immunodeficiency virus type I integration. Curr Opin HIV AIDS. 1:212–217.36Abbreviations: PIC, preintegration complex; LTRs, long terminal repeats.
Mentions: Integrase is an HIV-1 enzyme that is essential for viral replication. Integrase catalyzes at least 3 reactions: 3′ processing, formation of the preintegrase complex, and strand transfer (Figure 2). Briefly, once the viral RNA is retrotranscribed into DNA by reverse transcriptase, integrase removes a 3’ terminal portion at both ends of the newly formed DNA where it remains bound, stabilizing the preintegrase complex. Once 3’ processing occurs, the preintegrase complex can form which consists of ring-shaped viral DNA with associated virus and host proteins. This complex structure is able to translocate across the nuclear membrane and into the nucleus. The final reaction catalyzed by integrase is the strand transfer where both 3’ ends of the DNA are inserted into the host DNA or chromosome. The newly altered host DNA, which now includes the HIV DNA, requires repair which is done with cellular DNA repair enzymes. If strand transfer in inhibited, the viral ring structures remain in the nuclear cytoplasm, the clinical relevance of which is unknown.11–12 Inhibitors of integrase that have now been developed are strand transfer inhibitors (INSTIs) that block the insertion position on the host DNA. Three integrase inhibitor classes of compounds have been identified: diketoacids, hydroxyquinolones, and polyphenols. Raltegravir is a member of the diketoacid class and elvitegravir belongs to the hydroxyquinolone class.14

Bottom Line: Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development.Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed.The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

View Article: PubMed Central - PubMed

Affiliation: Pierre et Marie Curie Université - Paris 6, Service de Maladies Infectieuses et Tropicales, Paris, France.

ABSTRACT
Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development. Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed. Two drugs in this class have reached late stages of development for use in HIV-1 infected individuals: raltegravir, which has just been approved for use in treatment-experienced patients, and elvitegravir, currently in phase III trials. Both are potent with an IC(50) in the 30 nM range and active in vitro against wild type as well as in strains highly resistant to all other existing classes of drugs. Clinical trials in both treatment-naïve and -experienced patients have demonstrated raltegravir to be highly effective with an excellent tolerability profile and no specific clinical or metabolic side effects. Longer follow up is necessary to ensure this early safety profile is sustained. The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

No MeSH data available.


Related in: MedlinePlus