The dynamics of appearance and disappearance of HIV-1 integrase mutations during and after withdrawal of raltegravir therapy

Ferns, R. Bridget; Kirk, Stuart A.; Bennett, Julie; Williams, Ian; Edwards, Simon; Pillay, Deenan

doi:10.1097/qad.0b013e32832ec4ae

Cited by 32 publications

(28 citation statements)

References 18 publications

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“…While a range of different mutations have been associated with resistance to RAL (reviewed in reference 33), resistance generally evolves in a stepwise process via one of several potential pathways. The mutually exclusive primary resistance mutations N155H, Q148H/R/K, and, more rarely, Y143R/C/H provide some resistance to RAL (9,14,15,28). These primary mutations often are associated with secondary mutations specific to each primary mutation pathway, which increase RAL resistance and may restore fitness defects caused by primary mutations (15).…”

Section: Stimulated Cd4mentioning

confidence: 99%

Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages

Marsden

Avancena

Kitchen

et al. 2011

Antimicrob Agents Chemother

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CD4؉ T cells and macrophages are the primary target cells for HIV in vivo, and antiretroviral drugs can vary in their ability to inhibit the infection of these different cell types. Resistance pathways to the HIV integrase inhibitor raltegravir have previously been investigated in T cells. Primary raltegravir resistance mutations, most often at integrase amino acid position 148 or 155, afford some resistance to the drug. The acquisition of pathway-specific secondary mutations then provides higher-level resistance to viruses infecting T cells. We show here that during macrophage infection, the presence of a single primary raltegravir resistance mutation (Q148H, Q148R, N155H, or N155S) is sufficient to provide resistance to raltegravir comparable to that seen in viruses expressing both primary and secondary mutations in costimulated CD4؉ T cells. These data implicate macrophages as a potential in vivo reservoir that may facilitate the development of resistance to raltegravir. Notably, the newer integrase inhibitor MK-2048 effectively suppressed the infection of all raltegravir-resistant viruses in both T cells and macrophages, indicating that more recently developed integrase inhibitors are capable of inhibiting infection in both major HIV cellular reservoirs, even in patients harboring raltegravir-resistant viruses.

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Section: Stimulated Cd4mentioning

confidence: 99%

Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages

Marsden

Avancena

Kitchen

et al. 2011

Antimicrob Agents Chemother

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“…39,41 In some early treatment failures, virus populations containing N155H alone were observed to switch to virus populations with Q148R or H. Additional studies have also documented the dynamics of RAL resistance and the evolution of N155N/H to Q148H or N155H to Y143R in subjects with incomplete viral suppression. 45 The observation of InSTI resistance evolution during virologic failure may suggest that remaining on a RAL regimen could mitigate future therapeutic options within the InSTI class. However, some studies have suggested RAL may have persistent immunologic and virologic benefi t even after the development of resistance.…”

Section: Clinical Observations: Virologic Failure and Resistancementioning

confidence: 99%

Resistance to inhibitors of the human immunodeficiency virus type 1 integration

Hazuda¹

2010

Braz J Infect Dis

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“…Resistance mutations common to both of these first-generation integrase inhibitors have been reported and can result in high levels of drug resistance (26). Mutations which engender crossresistance between RAL and EVG have been reported in clinical trials, cell culture studies, and biochemical assays (9,26). This has prompted the search for second-generation integrase inhibitors that might display novel patterns of resistance, allowing their use in patients who have failed therapy with RAL or EVG.…”

mentioning

confidence: 99%

Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

Bar-Magen

Sloan

Donahue

et al. 2010

J Virol

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MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to firstgeneration INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to Ϸ13% of wt levels and increased resistance to MK-2048 to Ϸ8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer "off" rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg 2؉ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.Selective pressure exerted by antiretroviral drugs, in conjunction with high viral mutation rates, promotes the inevitable emergence of drug-resistant HIV-1 variants. This necessitates an ongoing search for novel antiretroviral compounds that either have novel mechanisms and inhibit different stages of viral replication or inhibit targets that have acquired resistance to existing drugs. In the latter case, such newer next-generation agents should ideally display resistance profiles which are distinct and nonoverlapping with those of the first-generation drugs.Integration of viral cDNA into the host cell genome is a distinct feature of retroviral replication, and inhibitors of HIV-1 integrase have recently been added to the arsenal of clinically approved antiretroviral drugs. Raltegravir (RAL) was the first integrase strand transfer inhibitor (INSTI) to be approved by the U.S. Food and Drug Administration (FDA) after clinical trials showed that this drug promoted a rapid and sustained antiviral effect (13). Elvitegravir (EVG), another integrase inhibitor, is currently in phase III clinical trials (27). Resistance mutations common to both of these first-generation integrase inhibitors have been reported and can result in high levels of drug resistance (26). Mutations which engender crossresistance between RAL and EVG have been reported in clinical trials, cell culture studies, and biochemical assays (9,26). This has prompted the search for second-generation integrase inhibitors that might display novel patterns of resistance, allowing their use in patients who have failed therapy with RAL or E...

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The dynamics of appearance and disappearance of HIV-1 integrase mutations during and after withdrawal of raltegravir therapy

Cited by 32 publications

References 18 publications

Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages

Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages

Resistance to inhibitors of the human immunodeficiency virus type 1 integration

Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

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