Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road NE, MS G-19, Atlanta, GA 30333, USA
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Abstract |
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Keywords: revertant viruses , fitness , virus evolution
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Introduction |
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Drug-resistant viruses can also be transmitted between individuals. Primary or transmitted resistance has been documented through vertical, sexual and parenteral routes.4 The proportion of patients newly infected with drug-resistant HIV-1 has increased during the past few years, and current estimates indicate that between 10% and 20% of acutely or recently infected persons in the USA and Europe have viruses that are resistant to one or more drugs.4 Infection with drug-resistant HIV-1 is of clinical and public health concern. Persons infected with drug-resistant viruses show a longer time to viral suppression and a shorter time to virological failure following initiation of antiretroviral therapy compared with patients infected with wild-type viruses.4
To date, more than 90 mutations have been associated with drug resistance. The list of mutations is periodically updated by the International AIDS SocietyUSA Drug Resistance Mutation Group.5 Mutations are identified by several criteria including in vitro selection with increasing concentrations of the antiviral drug, studies with site-directed mutants, susceptibility testing of laboratory or clinical isolates, selection in persons receiving antiretroviral drugs, and correlation studies between genotype and virological responses.5
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Evolution of drug resistance in treated and untreated persons |
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Viral adaptation to antiretroviral drug pressure is characterized by the initial selection of deleterious mutations that generally decrease drug susceptibility and viral fitness (Figure 1). Such mutations are commonly known as primary or major and are relatively specific for each drug. The deleterious effect of primary mutations is efficiently reduced by the selection of additional compensatory mutations known as secondary or minor.8 Such compensatory evolution usually results in a restoration of the structure and/or function of the RT or protease and generally increases the level of drug resistance. For instance, selection of D67N, K219Q and K70R in viruses carrying the T215Y mutation increases the levels of phenotypic resistance to zidovudine and enhances DNA synthesis by mutant RT enzymes.9 In some cases, selection of compensatory mutations is not associated with increased levels of drug resistance. For instance, PI-resistant mutants carrying M36I, I54V and V82T acquire A71V and K20R to compensate for a reduced protease catalytic activity but show no detectable increases in resistance to ritonavir.10 Compensatory evolution has also been observed outside the RT and protease gene. Such is the case for mutations at Gag and GagPol protease cleavage sites observed during treatment with protease inhibitors which are associated with improved enzyme kinetics.11 However, despite the accumulation of compensatory mutations, drug-resistant viruses generally display a reduced fitness compared with wild-type viruses.1113 Reductions in viral fitness and replication capacity of drug-resistant viruses have been associated with sustained immunological responses in patients who fail antiretroviral therapy, suggesting that viruses with low replication capacity might be less pathogenic.12
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Thymidine analogue-associated mutations (TAMs) |
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Although TAMs are usually selected by zidovudine and stavudine-containing regimens, recent studies indicate that these mutations are also associated with phenotypic and clinical resistance to each of the other nucleoside RT inhibitors (NRTIs) with the possible exception of lamivudine.21 The magnitude of phenotypic and clinical resistance to other NRTIs appears to be related to the number of TAMs. Complete loss of responses to abacavir usually requires the presence of three or more TAMs along with the M184V mutation, and four or more TAMs are needed for a complete loss of virological response to the addition of didanosine to a stable regimen.22 Specific patterns of TAMs may have a different impact on treatment responses. For instance, responses to tenofovir are less affected by the combination of D67N, K70R, K219Q/E and T215F than by the combination of M41L, L210W and T215Y.23 The magnitude of thymidine analogue resistance conferred by TAMs can also be modulated by other nucleoside analogue mutations. Such is the case for the M184V mutation commonly seen in regimens containing lamivudine or emtricitabine which causes high-level resistance to lamivudine and emtricitabine, moderate resistance to didanosine and abacavir, and increases the susceptibility to zidovudine, stavudine and tenofovir.21
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Reversion of TAMs in transmitted HIV-1 generates new genotypes with distinct properties |
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The establishment of new RT genotypes and the potential for secondary transmission heighten the importance of evaluating the impact of these mutants on resistance evolution. A rapid evolution towards zidovudine or stavudine resistance was first noted in vitro in transmitted isolates carrying 215D/C, and was explained by the need for only one nucleotide change to evolve from 215D/C to 215Y/F, as opposed to the two nucleotides required for wild-type viruses (Figure 2).25,26 Clinical studies have also suggested that the presence of the 215D/C substitutions may be associated with an increased risk of virological failure in antiretroviral-naive adults starting therapy with zidovudine or stavudine.31 A similar rapid evolution towards zidovudine resistance was recently noted in revertant viruses carrying D67N or K219Q (Figure 2). Interestingly, the rapid selection of zidovudine resistance in these viruses was associated with a high viral fitness in the presence of zidovudine.27 The high fitness of these viruses with zidovudine suggests a low level of phenotypic resistance that is not detected by the most sensitive phenotypic assays.
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The in vitro analysis of the evolution of zidovudine resistance in revertant viruses has illustrated how these new RT genotypes can influence the selection of specific drug resistance pathways. For instance, selection of zidovudine resistance in viruses with 215D/C was found to occur through acquisition of 215Y and not K70R, although both D/C215Y and K70R require a single nucleotide change.26 The preferential selection of 215Y seen in these viruses might be due to the higher levels of zidovudine resistance conferred by 215Y compared with K70R, or the presence of other mutations that are clinically associated with T215Y and not K70R. In contrast, the selection of K70R and not T215Y in transmitted isolates with D67N or K219Q may probably reflect the number of mutations required for each amino acid change (e.g. one nucleotide change for K70R compared with two nucleotides for T215Y/F). It is also possible that the presence of D67N and K219Q/E might favour selection of K70R over T215Y, since 67N and 219Q/E are more strongly associated in clinical isolates with K70R than with T215Y.32 These findings illustrate how newly generated RT backgrounds can influence selection of different patterns of TAMs which might be associated with variable clinical outcomes.23
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Impact of reversion on surveillance of transmitted resistance |
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Acknowledgements |
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References |
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