HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro

Roquebert, Bénédicte; Damond, Florence; Collin, Gilles; Matheron, Sophie; Peytavin, Gilles; Bénard, Antoine; Campa, Pauline; Chêne, Geneviève; Brun‐Vézinet, Françoise; Descamps, Diane

doi:10.1093/jac/dkn335

Cited by 111 publications

(91 citation statements)

References 22 publications

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“…In contrast, relatively large FC spectra were determined for the INSTIs. As previously reported (21,38,40), RAL and EVG each potently inhibited infection by HIV-2 and SIVmac. RAL potently inhibited MLV (1), while EVG acted moderately, with an FC of 39.…”

supporting

confidence: 82%

“…Protease inhibitors harbor an intermediate phenotype which is highly active against HIV-2/SIV (18) but ineffective against the Gammaretrovirus xenotropic murine leukemia virus-related virus (42). RAL and EVG were previously shown to be effective against HIV-2/SIV (21,38,40), gammaretroviruses (1,34,40,42,43), and the Spumavirus prototype foamy virus (PFV) (48), suggesting that they, like NRTIs, might harbor pantropic antiretroviral activities. To comprehensively address this question, we determined RAL and EVG concentrations required to inhibit infection by vectors derived from five different lentiviruses, the Betaretrovirus Mason-Pfizer monkey virus (MPMV), the Alpharetrovirus Rous sarcoma virus (RSV), and the Gammaretrovirus Moloney murine leukemia virus (MLV).…”

mentioning

confidence: 99%

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Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.Reverse transcription of retroviral RNA yields linear viral DNA (vDNA) containing a copy of the long terminal repeat (LTR) at each end. Integrase (IN) is an essential retroviral enzyme that catalyzes two reactions to insert the vDNA into cellular chromosomal DNA. IN prepares the LTR ends by hydrolyzing phosphodiester bonds adjacent to invariant CA dinucleotides, yielding reactive 3Ј deoxyadenylate (dA OH ) termini. In the nucleus, IN catalyzes DNA strand transfer by using the 3Ј OHs to cut the chromosome in a staggered fashion, concomitantly joining the vDNA ends to 5Ј phosphates. Hostmediated repair of the resulting DNA recombination intermediate completes the integration process. See reference 8 for an overview of retroviral reverse transcription and integration.IN belongs to the polynucleotidyl transferase superfamily of nucleic acid-metabolizing enzymes (7). Conserved amino acid residues (typically Asp and Glu [32]) arranged commonly on an RNase H structural fold comprise active sites that coordinate divalent metal ions for in-line nucleophilic attack of phosphodiester bonds. Due to its critical role in replication, human immunodeficiency virus type 1 (HIV-1) IN has long been targeted for drug development, and the first-in-class inhibitor raltegravir (RAL) was licensed in 2007 (45). Because RAL and related compounds preferentially inhibit DNA strand transfer activity, the drugs are referred to as IN strand transfer inhibitors (INSTIs) (24). Elvitegravir (EVG) is another well-studied INSTI (41). Recently determined X-ray crystal structures revealed that the drugs work by ejecting the 3Ј dA and its associated OH nucleophile from the IN active site (10,

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confidence: 82%

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confidence: 99%

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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“…However, little is known about the potential use of INIs in HIV-2-infected patients. A recent study showed that the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1 despite a 40% difference in sequence between the HIV-1 and HIV-2 integrase genes (73). This may be because certain key catalytic motifs (i.e., the DDE triad and the HHCC and RKK motifs) were fully conserved in HIV-2 at the genomic positions described for HIV-1 (73).…”

Section: Hiv-2 Resistance To Inismentioning

confidence: 99%

Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2

Ntemgwa

Toni

Brenner

et al. 2009

Antimicrob Agents Chemother

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“…All strains assessed in the study were issued from distinct HIV-2-infected maraviroc-naïve patients of the French Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) HIV-2 cohort (CO 05) and were isolated by cocultivation of the phytohemagglutinin (PHA)-activated peripheral blood mononuclear cell (PBMC) pool obtained from healthy blood donors, as previously described (15). Written consent was provided by all patients at the time of inclusion in the French ANRS CO 05 HIV-2 cohort.…”

Section: Methodsmentioning

confidence: 99%

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

Visseaux

Charpentier

Hurtado-Nédelec

et al. 2012

Antimicrob Agents Chemother

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HIV-2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors, to a fusion inhibitor, and to some of the protease inhibitors. Maraviroc is the first drug of the new anti-CCR5 drug class and is effective only on CCR5-tropic (R5) HIV-1. No previous studies concerning HIV-2 susceptibility to maraviroc have been reported yet. We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell (PBMC) model. We analyzed the maraviroc susceptibility of 13 R5 HIV-2, 2 X4R5 (dual) HIV-2, and 2 CXCR4-tropic (X4) HIV-2 clinical isolates. We also tested, with the same protocol, 1 X4 HIV-1 and 4 R5 HIV-1 clinical isolates. For the R5 HIV-2 clinical isolates, the 50% effective concentration (EC 50 ) for maraviroc was 0.80 nM (interquartile range [IQR], 0.48 to 1.39 nM), similar to that observed for the R5 HIV-1 isolates. The median maximum percentage of inhibition in the R5 HIV-2 isolates was 93% (IQR, 84 to 98%), similar to that observed in the R5 HIV-1 isolates. As expected, both X4 HIV-1 and HIV-2 were highly resistant to maraviroc. Our study showed for the first time that maraviroc is active in vitro against R5 HIV-2. The new tools we developed will allow identification of HIV-2-infected patients eligible for CCR5 inhibitor use and management of virological failure when receiving a maraviroc-based regimen.

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HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro

Cited by 111 publications

References 22 publications

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2

In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

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