High frequency of selection of K65R and Q151M mutations in HIV‐2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen

Descamps, Diane; Damond, Florence; Matheron, Sophie; Collin, Gilles; Campa, Pauline; Delarue, Séverine; Pueyo, Sophie; Chêne, Geneviève; Brun‐Vézinet, Françoise

doi:10.1002/jmv.20174

Cited by 64 publications

(58 citation statements)

References 29 publications

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“…Wild-type HIV-2 RT contains Ser instead of Thr at position 215, and only one nucleotide change is needed to obtain the substitution S215Y. However, Q151M emerges as the major AZT resistance mutation in HIV-2 RT, whereas TAMs are relatively uncommon in HIV-2-infected patients (72)(73)(74). Molecular modeling studies suggested that several amino acid differences around the putative ATP binding site of HIV-2 RT in comparison with the HIV-1 RT could account for these differences (75).…”

Section: Discussionmentioning

confidence: 99%

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

Matamoros

Nevot

Martı́nez

et al. 2009

Journal of Biological Chemistry

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Val75 of HIV-1 reverse transcriptase (RT) plays a role in positioning the template nucleotide ؉1 during the formation of the ternary complex. Mutations, such as V75M and V75A, emerge in patients infected with HIV-1 group M subtype B and group O variants, after failing treatment with stavudine (d4T) and other nucleoside RT inhibitors. V75I is an accessory mutation of the Q151M multidrug resistance complex of HIV-1 RT and is rarely associated with thymidine analogue resistance mutations (TAMs). In vitro, it confers resistance to acyclovir. TAMs confer resistance to zidovudine (AZT) and d4T by increasing the rate of ATP-mediated excision of the terminal nucleotide monophosphate (primer unblocking). In a wild-type HIV-1 group O RT sequence context, V75A and V75M conferred increased excision activity on d4T-terminated primers, in the presence of PP i . In contrast, V75I decreased the PP i -mediated unblocking efficiency on AZT and d4T-terminated primers, in different sequence contexts (i.e. wild-type group M subtype B or group O RTs). Interestingly, in the sequence context of an excision-proficient RT (i.e. M41L/A62V/T69SSS/K70R/ T215Y), the introduction of V75I led to a significant decrease of its ATP-dependent excision activity on AZT-, d4T-, and acyclovir-terminated primers. The excision rate of d4T-monophosphate in the presence of ATP (3.2 mM) was about 10 times higher for M41L/A62V/T69SSS/K70R/T215Y than for the mutant M41L/A62V/T69SSS/K70R/V75I/T215Y RT. The antagonistic effect of V75I with TAMs was further demonstrated in phenotypic assays. Recombinant HIV-1 containing the M41L/A62V/ T69SSS/K70R/V75I/T215Y RT showed 18.3-and 1.5-fold increased susceptibility to AZT and d4T, respectively, in comparison with virus containing the M41L/A62V/T69SSS/K70R/ T215Y RT.

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Section: Discussionmentioning

confidence: 99%

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

Matamoros

Nevot

Martı́nez

et al. 2009

Journal of Biological Chemistry

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“…In regard to the K65R mutation, several clinical studies reported a high frequency of the mutation in NRTI-treated patients infected with HIV-2 (13,14), whereas in other studies K65R was rarely observed (34)(35)(36). In addition, in vitro, the selection of K65R in HIV-2 is not common (37,38).…”

Section: Figmentioning

confidence: 99%

“…In HIV-2 patients failing therapy, V111I was previously reported to be coselected with mutation Q151M (14,15,20). Mutation Q151M alone was suggested to confer resistance to d4T and ABC, whereas resistance to other NRTIs would involve the coselection of V111I (20).…”

Section: Figmentioning

confidence: 99%

“…Several studies suggest that HIV-1 and HIV-2 evolve NRTI resistance by different mutational pathways. Although relying on limited amounts of genotypic data for HIV-2, three key resistance mutations, K65R, Q151M, and M184V, were reported to be associated with drug resistance (12)(13)(14)(15). The K65R and Q151M substitutions are more common in HIV-2 than in HIV-1 and often appear together with M184V in patients who received NRTI therapy.…”

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confidence: 99%

“…For instance, mutation V111I was reported to be coselected with mutation Q151M in HIV-2 patients failing therapy (14,15,20). 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).…”

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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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Antiretroviral Therapy and Drug Resistance in HIV-2 Infection

Brun‐Vézinet¹,

Matheron²,

Descamps³

2013

Encyclopedia of AIDS

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High frequency of selection of K65R and Q151M mutations in HIV‐2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen

Cited by 64 publications

References 29 publications

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

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

Antiretroviral Therapy and Drug Resistance in HIV-2 Infection

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