The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions

Abstract

It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.Antiretroviral drug resistance is an important cause of treatment failure in human immunodeficiency virus type 1-infected persons treated with reverse transcriptase (RT) and protease inhibitors. Emergence of resistance during treatment usually involves the initial selection of deleterious mutations that reduce drug susceptibility and decrease replicative capacity. Compensatory evolution through the acquisition of additional mutations generally results in partial restorations of viral fitness (19). Despite the accumulation of compensatory mutations, drug-resistant viruses tend to replicate less efficiently than wild-type viruses.The transmission of drug-resistant mutants with diminished fitness and the evolution of these viruses in the absence of drug are typically associated with the reversion and loss of resistance mutations (3,9,22). Different rates of persistence and reversion of mutations have been documented in vivo and have usually been explained by the impact of mutations on viral fitness. For instance, less-fit zidovudine-resistant mutants carrying T215Y/F are generally replaced by more-fit 215D/C/S revertants within less than a year, while more-fit M41L or D67N mutants tend to revert more slowly (1-3, 5, 6, 8, 13, 17, 20, 25). However, in vivo observations do not always show the expected relationship between fitness cost and persistence, and a range of persistence for the same mutation has been noted among patients infected with multidrug-resistant viruses. For instance, M184V mutants have been found to persist between 4 and 16 months after primary infection, while persistence of K103N can range between 1 and 3 years (2,3,5,17). We hypothesize that mutational interactions in multidrug-resistant viruses might modulate the fitness cost of resistance mutations and might influence the rate of reversion and persistence of mutations.

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

“…K65R, which confers resistance to the nucleotide analog tenofovir, has been shown to have a reduction in fitness when introduced into laboratory strains, as well as in the context of patient sequences, as measured by the Monogram Biosciences RC assay (35,46,179). Similar findings were also obtained using whole isolates obtained from patients failing tenofovir therapy (175).…”

“…M184V has a fitness similar to that of the wild type in most T-cell lines where nucleotide concentrations are high (10) but reduced fitness in primary cells that have limited nucleotide pools, such as PBMCs and macrophages (3,10,129). Of note is that there are some more-recent studies that have found reduced fitness of this mutant in cell lines (35,48).…”

“…In contrast, the Q151M complex did not reduce the fitness of M184V, suggesting that the combinations of nRTIs prescribed to the patient may influence whether the Q151M complex develops (66a). A recent report has demonstrated that the reduced fitness of M184V is improved when placed in combination with the TAM-2 cluster of mutations; no such effect is seen when M184V is combined with TAM-1 mutations (35). The two clusters of TAM mutations had opposite effects when combined with K70R (35).…”

“…L74V, which confers resistance to both didanosine and abacavir, has reduced fitness in studies of sitedirected mutants relative to wild-type virus and K70R using growth competition assays in primary human PBMCs and a cell line (35,154). It has been shown that L74V in the context of the NL4-3 laboratory strain has an 11% loss of fitness compared to that of the wild type or K70R (154).…”

Molecular characterisation of newly identified HIV-1 infections in Curitiba, Brazil: preponderance of clade C among males with recent infections

“…The NNRTI class has a low resistance barrier (single mutations may cause a significant decrease in drug susceptibility) and NNRTI based highly active treatment combinations are a popular initial regimens in the country as well in the WHO treatment program. The presence of K103N, the most common DRM observed, may be partially explained by the low impact on the viral fitness of this mutation, a fact that favours its persistence (Cong et al 2007). Another mutation associated with NNRTI, at codon P236, probably represents a natural polymorphism, unrelated to primary resistance secondary to transmission, as Delavirdine is rarely used in this area and Efavirenz and Nevirapine do not select for this mutation.…”