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The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir

Oliveira, Maureen; Ibanescu, Ruxandra I.; Pham, Hanh Thi; Brenner, Bluma; Mesplède, Thibault; Wainberg, Mark A.

doi: 10.1097/QAD.0000000000001191

Objective: Recommended treatments for newly diagnosed HIV-positive individuals now focus on the integrase strand transfer inhibitors, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). In treatment-naive individuals, cases of RAL-based and EVG-based virological failure, although rare, are associated with the occurrence of resistance mutations in integrase and/or reverse transcriptase coding sequences. In such cases, common resistance substitutions in reverse transcriptase that were associated with nucleos(t)ide reverse transcriptase inhibitors included M184I/V and K65R and these occurred together with various mutations in integrase. In some instances, these mutations in reverse transcriptase preceded the emergence of mutations in integrase. In contrast, no resistance substitutions in either integrase or reverse transcriptase have been observed to date in viruses isolated from treatment-naive individuals who experienced treatment failure with DTG-based regimens.

Design: The objective of this study was to determine the effects of the M184I/V and K65R substitutions in reverse transcriptase on the ability of HIV-1 to become resistant against RAL, EVG or DTG.

Methods: We performed tissue culture selection experiments using reverse transcriptase inhibitor-resistant viruses containing resistance substitutions at positions K65R, M184I or M184V in the presence of increasing concentrations of RAL, EVG or DTG and monitored changes in integrase sequences by genotyping.

Results: Selections using EVG and RAL led to the emergence of resistance mutations in integrase. In contrast, only the wild-type virus was able to acquire resistance mutations for DTG.

Conclusion: Resistance mutations against nucleos(t)ide reverse transcriptase inhibitors antagonized the development of HIV-1 resistance against DTG but not RAL or EVG.

aMcGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital

bDivision of Experimental Medicine

cDepartment of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.

Correspondence to Mark A. Wainberg, McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Côte-Ste-Catherine, Montréal, Québec, Canada H3T1E2. E-mail:

Received 29 March, 2016

Revised 24 May, 2016

Accepted 21 June, 2016

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HIV drug resistance can have dire consequences for infected individuals and imposes a high financial burden on healthcare systems throughout the world. In addition, drug-resistant viruses can threaten long-term treatment strategies as well as efforts to prevent transmission through use of preexposure prophylaxis [1–3]. Resistance mutations have been documented against all antiretroviral drugs in use, including reverse transcriptase, protease and integrase inhibitors [4]. Well documented mutations against lamivudine (3TC) and tenofovir (TFV) include M184I/V and K65R, and drug resistance following first-line therapy has hitherto been reported for all drugs with the exception of the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG), for which resistance mutations have only been reported in the case of treatment-experienced individuals [5–8], whereas first-line treatment failures following DTG-based therapy have thus far not included resistance mutations in either the integrase or reverse transcriptase coding sequences [9–15]. This relative nonsusceptibility of DTG to drug resistance in treatment-naive individuals may have implications for global health strategies [16–18].

At the same time, two other INSTIs, raltegravir (RAL) and elvitegravir (EVG), are also used for treatment of HIV-positive individuals, but unlike DTG, they have given rise to drug resistance mutations in rare cases of treatment failure in both treatment-naive as well as treatment-experienced individuals. These mutations commonly confer cross-resistance against both RAL and EVG, and involve changes at positions T66, E92, Y143, N155 and/or Q148. Modelling studies suggest that the latter residue lies at the centre of the HIV integrase catalytic core [19,20] and Q148 substitutions plus two or more mutations that are often found following treatment failure with RAL/EVG have been shown to increase the likelihood of subsequent treatment failure with DTG [6]. Similarly, RAL/EVG-associated resistance substitutions at position N155H or G118R can also decrease the subsequent efficacy of second-line or third-line DTG-based therapy [21,22].

Altogether, the clinical data suggest that previous exposure to RAL or EVG can lower the benefits of suboptimal DTG-based treatment, for example when DTG is used as monotherapy in switch studies or together with suboptimal background regimens, independently of whether preexisting mutations in integrase were detected or not [18,23]. In treatment-experienced, integrase inhibitor-naive individuals who experienced treatment failure while taking DTG, the R263K substitution in integrase was the most common de novo mutation detected [5] and had also been selected by DTG through tissue culture passage [24].

The R263K substitution reduces viral integration and fitness and has not been associated with compensatory secondary substitutions in vitro or in HIV-positive individuals [18,24–27]. Nor is emergence of R263K in viruses isolated from individuals who experienced DTG treatment failure associated with the presence of resistance mutations in reverse transcriptase [5]. In contrast, treatment failure with RAL is commonly associated with emergent mutations in either integrase or reverse transcriptase or both, whereas failure with EVG is commonly associated with the presence of resistance mutations in both integrase and reverse transcriptase (reviewed in [28]). Detailed genotypic analyses following EVG treatment failure showed that resistance mutations in reverse transcriptase often preceded the emergence of resistance mutations in integrase [29]. For this reason, we investigated the effects of the common K65R, M184I and M184V mutations that confer resistance against nucleos(t)ide reverse transcriptase inhibitors (NRTIs) on the emergence of resistance against RAL, EVG and DTG in tissue culture. Our results show that these NRTI-resistant mutations prevented the facile emergence of resistance mutations against DTG but not against RAL or EVG. This work helps to explain the absence of resistance mutations in most individuals who experienced treatment failure while on first-line DTG-based therapy.

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Cells and reagents

Primary human cord blood mononuclear cells (CBMCs) isolated from cord blood obtained through the Department of Obstetrics, Jewish General Hospital, Montréal, Canada and isolated by Ficoll Hypaque (GE Healthcare Life Sciences, Baie-d’Urfé, Quebec, Canada) were stimulated with phytohaemagglutinin for 48 h prior to infection. Merck & Co., Inc. (Kenilworth, New Jersey, USA), Gilead Sciences, Inc. (Foster City, California, USA) and ViiV Healthcare Inc. (Research Triangle Park, North Carolina, USA) kindly provided RAL, EVG and DTG, respectively. 3TC and TFV were obtained through the National Institutes of Health (NIH) AIDS Reagent Program.

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Selection of resistant viruses in cord blood mononuclear cells

Following activation, CBMCs were infected with K65R-containing, M184I-containing or M184V-containing viral isolates and grown in RPMI1640 medium supplemented with 10% FBS (Life Technologies, Thermo Fisher Scientific, Mississauga, Ontario, Canada) in the presence of increasing RAL, EVG or DTG concentrations, as described previously [11]. Viruses were produced from previously described pNL4.3 plasmids that were generated by site-directed mutagenesis [30,31]. In addition, infections with M184I, M184V and K65R viruses were performed in the presence of 2.5 nmol/l 3TC, 50 nmol/l 3TC and 50 nmol/l TFV, respectively, to prevent reversions in reverse transcriptase coding sequences. HIV-1 replication was measured through weekly quantification of reverse transcriptase activity in culture fluids in the presence and absence of drug. Drug concentrations were raised by 2.5-fold when levels of replication in the presence of antiviral compound were similar to those in the absence of drug. Otherwise, drug concentrations remained unchanged.

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Nucleic acid extraction, amplification and sequence analysis

Emerging resistance mutations in integrase were detected by extraction of viral RNA from culture fluids using the QIAamp Viral RNA Extraction kit (Qiagen, Toronto, Ontario, Canada), followed by reverse transcription, amplification by PCR and sequencing, as previously described [32]. No additional mutations in reverse transcriptase were observed during our tissue culture selection experiments.

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Development of phenotypic resistance against raltegravir, elvitegravir or dolutegravir using wild-type, M184I, M184V and K65R viruses

First, we monitored the concentrations of DTG, EVG or RAL at which the wild-type (WT) and various mutated HIV-1 viruses were able to replicate over time (Fig. 1). The WT virus was able to grow in the presence of increasing RAL or EVG concentrations more easily than in the presence of DTG (Fig. 1a). After 20 weeks of culture, RAL, EVG and DTG concentrations were 0.5 μmol/l, 0.5 μmol/l and 25 nmol/l, respectively. When the M184I virus was used, drug concentrations at week 20 could only be increased to 10, 5 and 10 nmol/l for RAL, EVG and DTG, respectively (Fig. 1b), and the DTG concentration could only be raised to 25 nmol/l at week 21. When infections were initiated with the M184V virus, the concentrations of RAL and EVG could be raised progressively and reached 0.5 and 0.25 μmol/l, respectively, after 20 weeks of culture (Fig. 1c). In contrast, DTG levels could only be elevated to 10 and 25 nmol/l after 20 and 21 weeks of culture, respectively. The presence of the K65R resistance substitution allowed increases in drug concentrations to 25 nmol/l RAL, 250 nmol/l EVG and 10 nmol/l DTG after 20 weeks of culture (Fig. 1d).

Fig. 1

Fig. 1

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The K65R, M184I and M184V substitutions impair the emergence of dolutegravir resistance mutations

Next, we monitored the emergence of mutations in the integrase coding region by sequencing at different time points (Table 1). These analyses revealed the absence of resistance mutations in integrase at all times when tissue culture selection experiments were performed with the K65R, M184I or M184V viruses under DTG pressure. In contrast, the WT virus possessed the R263K integrase substitution at weeks 17 and 22 in agreement with previous in-vitro and clinical studies [5,24,33]. The T66I substitution in integrase was detected with both RAL and EVG when the M184I virus was propagated for 22 and 12 weeks, respectively. The same substitution was also found with the M184V and K65R viruses in the presence of EVG. The use of RAL led to the emergence of either the N155H or Y143H substitutions when the M184V or K65R viruses, respectively, were studied. The WT virus accumulated several integrase resistance mutations in the presence of either EVG or RAL.

Table 1

Table 1

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Previous clinical studies showed that treatment failure with EVG-based antiretroviral regimens was associated in some cases with the initial emergence of reverse transcriptase resistance mutations followed by integrase mutations [29]. In contrast, no resistance mutation in either reverse transcriptase or integrase has yet been reported in viruses that were isolated from treatment-naive individuals who experienced treatment failure with DTG [9–14]. Although de novo resistance has not been observed in clinical trials with treatment-naive individuals taking DTG, we cannot overlook the possibility that relevant mutations may eventually be observed in ‘real-life’ settings. In particular, virological failure is usually detected early in clinical trials; as a result, genotyping is also performed early and might precede the emergence of detectable de novo resistance mutations. However, DTG has now been available for general use for almost 3 years, and there has not been a single published report of de novo resistance mutation against this drug in treatment-naive individuals. Whether this situation will persist remains controversial and has important implications for the future of the HIV epidemic [18]. Virological failure in the absence of resistance mutations has been observed in individuals who report high levels of adherence to treatment and/or possess high drug concentrations in their blood. The reason for this remains unknown but may involve uncharacterized drug–drug interactions and/or pharmacogenomics or metabolic interindividual differences. Alternatively, spontaneous or T-cell receptor specific reactivation of latently infected CD4+ T cells may contribute to this phenomenon. Future studies could assess whether individuals with large reservoirs are at high risk of virological failure without mutations despite high-level adherence.

Here, we investigated the effects of the M184I, M184V and K65R mutations that confer resistance against 3TC and TFV on the emergence of resistance against RAL, EVG or DTG. Our results demonstrate that those NRTI-resistant HIV-1 viruses were unable to acquire resistance mutations against DTG, whereas the WT virus was able to acquire the R263K substitution under DTG pressure (Table 1). One limitation of our study is that other NRTI resistance mutations may not have yielded results similar to those of the K65R and M184I/V viruses. Indeed, other resistance substitutions in reverse transcriptase can also negatively impact HIV replication and DNA integration when combined with R263K [30]. This raises the possibility that mutations other than K65R and M184I/V may negatively affect the emergence of R263K in tissue culture. In addition, different HIV subtypes may possibly behave differently in regard to R263K emergence.

Although rare, the K65R + M184I/V combinations of substitutions can be observed in individuals who experience treatment failure with either INSTI-based or non-INSTI-based regimens. K65R + M184I/V combinations were reported in viruses isolated from 4/18 individuals who developed resistance mutations while participating in the 102 and 103 clinical trials [34]. We did not examine the effect of combining K65R and M184I/V substitutions on tissue culture selection experiments with RAL, EVG or DTG. However, given that K65R and M184I/V do not compensate each other, we would expect that selection studies with K65R + M184I/V viruses should yield results similar to those obtained with viruses bearing either substitution, that is an absence of resistance mutations in the presence of DTG. Studies of DTG monotherapy suggest that this drug is effective at suppressing viral loads when used as a single antiretroviral agent [22,35–40], raising the possibility that DTG may be beneficial to individuals infected with K65R + M184I/V viruses, so long as such individuals are not infected with viruses with INSTI resistance mutations. Future experiments should investigate how the K65R + M184I/V substitutions may influence tissue culture selections with DTG.

Using WT virus, the data show that two populations could be identified at week 17 under DTG pressure, with both S153F/S and R263K/R mixtures having emerged at that time. However, only R263K was present after 22 weeks. Loss of the S153F/S mixture concomitantly with the establishment of the R263K substitution between weeks 17 and 22 may have been due to either reversion or loss of the S153F substitution. We did not perform clonal analyses of these viruses. However, given that R263K diminishes HIV evolutionary capacity [41], we hypothesize that the S153F substitution emerged independently of R263K before being lost. Further studies are needed to test whether R263K outcompeted S153F because of higher levels of resistance or superior replication capacity. In comparison, resistance mutations for both RAL and EVG emerged from the WT as well as NRTI-resistant viruses (Table 1). In agreement with clinical data that showed that substitutions at position T66 were more common following treatment failure with EVG than RAL, this substitution was detected in eight of eight sequences when infections were performed in the presence of EVG, in most cases in association with other resistance mutations (Table 1). Viral propagation in the presence of RAL was also associated with the emergence of various substitutions, including T66I/T, T97A, Y143R/H or N155H. Among all the reverse transcriptase substitutions studied, M184I seemed to have the greatest inhibitory effect on the emergence of resistance mutations in integrase. When this substitution was present, EVG, RAL and DTG drug concentrations could be raised to 5, 10 and 25 nmol/l, respectively (Fig. 1). Although this may seem to suggest that the M184I virus can become more resistant to DTG than to either RAL or EVG, we did not observe any mutation under DTG pressure, whereas the T66I substitution was found with both RAL and EVG. This underlines the importance of monitoring both drug levels and mutations when performing tissue culture experiments.

One limitation of our study is that 3TC or TFV was added to the culture media in some experiments in which NRTI-resistant viruses were propagated to prevent reversion of the reverse transcriptase mutations. Although high levels of synergy between TFV/emtricitabine and RAL or EVG have been reported in vitro[42], similar studies have not been performed with DTG. It remains unknown whether synergy levels between DTG and 3TC/TFV are superior to those between EVG or RAL and 3TC/TFV, and whether this may have contributed to the absence of de novo mutations in NRTI-resistant viruses under DTG pressure (Table 1). However, if such differences exist, we believe that they are unlikely to have significantly contributed to our results, as the weekly levels of reverse transcriptase activity produced by cells infected with WT or mutant viruses were similar throughout the study. This does not affect our main conclusion, which is that the K65R-containing, M184I-containing and M184V-containing viruses were able to develop resistance mutations against RAL and EVG but not against DTG.

The highest dose of DTG attained in our tissue culture experiments was 25 nmol/l (Fig. 1), a concentration that is below the reported protein-adjusted IC90 (64 ng/ml, 152 nM) for this drug [43,44]. In contrast, EVG concentrations could be raised to more than 250 nmol/l when infections were initiated with any of the WT, M184V or K65R viruses (Fig. 1), a level that is above its reported protein-adjusted IC95 (45 ng/ml, approximately 100.5 nmol/l) [43–45]. In contrast, the M184I virus was only able to grow in the presence of 5 nmol/l EVG. After 20 weeks, RAL concentrations reached 500, 10, 500 and 25 nmol/l for the WT, M184I-containing, M184V-containing and K65R-containing viruses, respectively, compared with a published protein-adjusted IC95 of 15 ng/ml or 33 nmol/l [46]. Although tissue culture experiments do not adequately reflect HIV-1 genetic evolution within the host [33], the fact that our experiments did not allow viral growth at DTG concentrations that were above the protein-adjusted IC90 is worth noting.

Altogether, the data suggest that DTG has a higher barrier to development of resistance than any of 3TC, TFV, RAL and EVG because of the inability of NRTI-resistant viruses to acquire resistance mutations against DTG (current study), the decreased ability of DTG-resistant viruses to become resistant against reverse transcriptase inhibitors [41] and the decreased viral replication capacity of viruses containing both the R263K and either K65R or M184I/V mutations [30,31]. This hypothesis is supported by the fact that no report has yet emerged of individuals who have failed first-line DTG-based therapy with resistance mutations in either reverse transcriptase or integrase, in spite of the fact that DTG was approved for therapy in the United States in July 2013 and has been used since that time to treat many thousands of individuals, including those coinfected by other viruses such as hepatitis C virus as well as those coming from nonaffluent hard-to-reach communities such as inner-city Washington, DC. The fact that reverse transcriptase mutations have not been observed in individuals who experienced treatment failure with DTG-based regimens is consistent with the results of this manuscript.

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M.O. performed tissue culture selection studies and analysed the data. R.I.I. performed sequencing analyses. H.T.P., B.B. and M.A.W. analysed the data. T.M. designed experiments, analysed data and wrote the manuscript. M.A.W. supervised the project and revised the manuscript. All authors read and approved the final manuscript.

The current project was supported by the Canadian Institutes for Health Research (CIHR).

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Conflicts of interest

There are no conflicts of interest.

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dolutegravir; drug resistance; integrase inhibitors; K65R; M184I/V; reverse transcriptase

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