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HIV integrase inhibitors: 20-year landmark and challenges.

ABSTRACT: Since the discovery of HIV as the cause for AIDS 30 years ago, major progress has been made, including the discovery of drugs that now control the disease. Here, we review the integrase (IN) inhibitors from the discovery of the first compounds 20 years ago to the approval of two highly effective IN strand transfer inhibitors (INSTIs), raltegravir (Isentress) and elvitegravir (Stribild), and the promising clinical activity of dolutegravir. After summarizing the molecular mechanism of action of the INSTIs as interfacial inhibitors, we discuss the remaining challenges. Those include: overcoming resistance to clinical INSTIs, long-term safety of INSTIs, cost of therapy, place of the INSTIs in prophylactic treatments, and the development of new classes of inhibitors (the LEDGINs) targeting IN outside its catalytic site. We also discuss the role of chromatin and host DNA repair factor for the completion of integration.

SUBMITTER: Metifiot M

PROVIDER: S-EPMC7569752 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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HIV integrase inhibitors: 20-year landmark and challenges.

Métifiot Mathieu M Marchand Christophe C Pommier Yves Y

Advances in pharmacology (San Diego, Calif.) 20130101

Since the discovery of HIV as the cause for AIDS 30 years ago, major progress has been made, including the discovery of drugs that now control the disease. Here, we review the integrase (IN) inhibitors from the discovery of the first compounds 20 years ago to the approval of two highly effective IN strand transfer inhibitors (INSTIs), raltegravir (Isentress) and elvitegravir (Stribild), and the promising clinical activity of dolutegravir. After summarizing the molecular mechanism of action of th ...[more]

PMID: 23885999

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Project description:Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We therefore set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs).We determined 337 HIV-1 integrase subtype B sequences (amino acids 1-278) from stored plasma samples of antiretroviral treatment-naïve individuals newly diagnosed with HIV-1 between 1986 and 2006. Shannon entropy was calculated to determine the variability at each amino acid position. Time trends in the frequency of amino acid variants were identified by linear regression. Direct coupling analysis was applied to detect covarying sites.Twenty-two time trends in the frequency of amino acid variants demonstrated either single amino acid exchanges or variation in the degree of polymorphy. Covariation was observed for 17 amino acid variants with a temporal trend. Some minor INSTI resistance mutations (T124A, V151I, K156 N, T206S, S230 N) and some INSTI-selected mutations (M50I, L101I, T122I, T124 N, T125A, M154I, G193E, V201I) were identified at overall frequencies >5%. Among these, the frequencies of L101I, T122I, and V201I increased over time, whereas the frequency of M154I decreased. Moreover, L101I, T122I, T124A, T125A, M154I, and V201I covaried with non-resistance-associated variants.Time-trending, covarying polymorphisms indicate that long-term evolutionary changes of the HIV-1 integrase involve defined clusters of possibly structurally or functionally associated sites independent of selective pressure through INSTIs at the inter-patient level. Linkage between polymorphic resistance- and non-resistance-associated sites can impact the selection of INSTI resistance mutations in complex ways. Identification of these sites can help in improving genotypic resistance assays, resistance prediction algorithms, and the development of new integrase inhibitors.

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HIV integrase inhibitors: 20-year landmark and challenges.

Publications

HIV integrase inhibitors: 20-year landmark and challenges.

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