Antiretroviral Drug Resistance in HIV‐2: Three Amino Acid Changes Are Sufficient for Classwide Nucleoside Analogue Resistance

Smith, Robert A.; Anderson, Donovan J.; Pyrak, Crystal L.; Preston, Bradley D.; Gottlieb, Geoffrey S.

doi:10.1086/597802

Cited by 60 publications

(71 citation statements)

References 26 publications

(19 reference statements)

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“…These mutations were found to reduce the incorporation of nucleotide analogues during reverse transcription in both HIV-1 (33) and HIV-2 (18). Consistent with previous studies, TAMs, which provide the principal route to NRTI resistance in HIV-1 by the excision pathway, were observed only at very low frequencies in the HIV-2 patients.…”

Section: Discussionsupporting

confidence: 87%

“…Mutation Q151M alone was suggested to confer resistance to d4T and ABC, whereas resistance to other NRTIs would involve the coselection of V111I (20). However, a previous in vitro study demonstrated that Q151M mediates resistance to AZT, d4T, and ddI (18). Resistance to these NRTIs was also measured in our study for Q151M.…”

Section: Figsupporting

confidence: 57%

“…Mutation M184V provides high-level resistance to 3TC, and K65R provides resistance to ddI, TDF, and 3TC. In the previous study (18), no increase in the IC 50 for TDF was measured for mutation K65R. This could be due to differences in the assay used to determine drug susceptibility.…”

Section: Figmentioning

confidence: 83%

“…This difference between HIV-1 and HIV-2 may be explained by the reduced ability of the HIV-2 RT enzyme to carry out the excision reaction using ATP-mediated pyrophosphorolysis (16,17). The individual contributions of the key resistance mutations K65R, Q151M, and M184V in HIV-2 were addressed using site-directed mutants in cell culture-based phenotypic assays (18). This study showed that the combination of the three mutations is sufficient for classwide NRTI resistance.…”

mentioning

confidence: 99%

“…A study using patient-derived HIV-2 isolates suggested that Q151M alone confers resistance only to stavudine (d4T) and abacavir (ABC), whereas resistance to other NRTIs involved the coselection of V111I (20). In contrast, another study showed that mutation Q151M alone is sufficient to produce high-level zidovudine (AZT) resistance, and therefore, V111I was not required for broad-spectrum NRTI resistance (18). Recent studies on HIV-1 suggest that mutations in the connection and RNase H domains of RT may contribute to NRTI and NNRTI resistance (for a review, see reference 21).…”

mentioning

confidence: 99%

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Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

Deuzing

Charpentier

Wright

et al. 2015

J Virol

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Infection with HIV-2 can ultimately lead to AIDS, although disease progression is much slower than with HIV-1. HIV-2 patients are mostly treated with a combination of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and protease inhibitors designed for HIV-1. Many studies have described the development of HIV-1 resistance to NRTIs and identified mutations in the polymerase domain of RT. Recent studies have shown that mutations in the connection and RNase H domains of HIV-1 RT may also contribute to resistance. However, only limited information exists regarding the resistance of HIV-2 to NRTIs. In this study, therefore, we analyzed the polymerase, connection, and RNase H domains of RT in HIV-2 patients failing NRTI-containing therapies. Besides the key resistance mutations K65R, Q151M, and M184V, we identified a novel mutation, V111I, in the polymerase domain. This mutation was significantly associated with mutations K65R and Q151M. Sequencing of the connection and RNase H domains of the HIV-2 patients did not reveal any of the mutations that were reported to contribute to NRTI resistance in HIV-1. We show that V111I does not strongly affect drug susceptibility but increases the replication capacity of the K65R and Q151M viruses. Biochemical assays demonstrate that V111I restores the polymerization defects of the K65R and Q151M viruses but negatively affects the fidelity of the HIV-2 RT enzyme. Molecular dynamics simulations were performed to analyze the structural changes mediated by V111I. This showed that V111I changed the flexibility of the 110-to-115 loop region, which may affect deoxynucleoside triphosphate (dNTP) binding and polymerase activity. IMPORTANCEMutation V111I in the HIV-2 reverse transcriptase enzyme was identified in patients failing therapies containing nucleoside analogues. We show that the V111I change does not strongly affect the sensitivity of HIV-2 to nucleoside analogues but increases the fitness of viruses with drug resistance mutations K65R and Q151M.

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Section: Discussionsupporting

confidence: 87%

Section: Figsupporting

confidence: 57%

Section: Figmentioning

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

Deuzing

Charpentier

Wright

et al. 2015

J Virol

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Molecular Diagnosis of HIV-1 Infections: Current State of the Art

Tang

2012

Advanced Techniques in Diagnostic Microbiology

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HIV-2 Infection, End-Stage Renal Disease and Protease Inhibitor Intolerance

Francisci

Martinelli

Weimer

et al. 2011

Clin. Drug Investig.

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Non-nucleoside reverse transcriptase inhibitors and enfuvirtide are ineffective against HIV-2 replication. These considerations may have particular significance in the formulation of second-line or salvage regimens for HIV-2 infection when resistance or toxicity precludes the use of protease inhibitors (PIs) or specific nucleoside analogues. We describe a case of a treatment-experienced patient with important limitations in therapeutic options dictated by the presence of HIV-2 infection, severe HIV nephropathy (requiring haemodialysis), intolerance to PIs and clinical contraindications to the use of some nucleoside analogues (anaemia, pancreatic toxicity and high cardiovascular risk). A three-drug regimen based on raltegravir, tenofovir disoproxil fumarate and lamivudine was given, with no major toxicity, good immunological response and complete viral suppression. Our case indicates that regimens based on integrase inhibitors could represent an effective alternative in PI-resistant or PI-intolerant patients with HIV-2, and that tenofovir disoproxil fumarate may be used in patients with end-stage renal disease requiring haemodialysis who cannot take other nucleoside analogues because of treatment-limiting adverse effects.

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Antiretroviral Drug Resistance in HIV‐2: Three Amino Acid Changes Are Sufficient for Classwide Nucleoside Analogue Resistance

Cited by 60 publications

References 26 publications

Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

Molecular Diagnosis of HIV-1 Infections: Current State of the Art

HIV-2 Infection, End-Stage Renal Disease and Protease Inhibitor Intolerance

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