Replicative fitness in vivo of HIV‐1 variants with multiple drug resistance‐associated mutations

Devereux, Helen; Emery, Vincent C.; Johnson, Margaret; Loveday, Clive

doi:10.1002/jmv.2023

Cited by 90 publications

(59 citation statements)

References 23 publications

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“…A difference between replication capacity and specific infectivity has been observed with several other mutant PRs (unpublished observation), indicating that this phenomenon is not restricted to the N88S class mutants. The magnitude of reduction of specific infectivity reported here for the N88S-carrying strain was similar to the reduction of PR catalytic efficiency to 20 to 40% of that found in the wild type, observed for a different mutation at position 88 linked to nelfinavir resistance (N88D) (17), and the relative fitness measurements were comparable to the 80% relative fitness observed in vivo for virus strains harboring the N88D substitution (7).…”

Section: Discussionsupporting

confidence: 84%

Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly

Resch¹,

Ziermann

Parkin

et al. 2002

J Virol

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The evolution of human immunodeficiency virus type 1 (HIV-1) strains with reduced susceptibility to protease inhibitors (PIs) is a major cause of PI treatment failure. A subset of subjects failing a therapy regimen containing the PI nelfinavir developed mutations at position 88 in the protease region. The N88S mutation occurring in some of these subjects induces amprenavir hypersusceptibility and a reduction of fitness and replication capacity. Here we demonstrate that substitutions L63P and V77I in protease, in combination, partially compensate for the loss of fitness, loss of replication capacity, loss of specific infectivity, and aberrant Gag processing induced by the N88S mutation. In addition, these mutations partially ablate amprenavir hypersusceptibility. Addition of mutation M46L to a strain harboring mutations L63P, V77I, and N88S resulted in a reduction of fitness and infectivity without changing Gag-processing efficiency, while amprenavir hypersusceptibility was further diminished. The ratio of reverse transcriptase activity to p24 protein was reduced in this strain compared to that in the other variants, suggesting that the M46L effect on fitness occurred through a mechanism different from a Gag-processing defect. We utilized these mutant strains to undertake a systematic comparison of indirect, single, cycle-based measures of fitness with direct, replicationbased fitness assays and demonstrated that both yield consistent results. However, we observed that the magnitude of the fitness loss for one of the mutants varied depending on the assay used.The rapid, error-prone replication of human immunodeficiency virus (HIV) allows viral populations in the host to adapt quickly to changing selective pressures. One example of this adaptability is the failure of antiretroviral therapy due to the emergence of virus populations with reduced drug susceptibility caused by well-defined mutations in the protease region. The majority of such resistance-associated mutations are rarely observed in the absence of drug selection and have therefore been hypothesized to be of lesser fitness than the predominant, drug-susceptible virus strains (15,16,35). Indeed, it has been possible to demonstrate an impairment of the catalytic efficiency and polyprotein precursor processing of protease (PR)-bearing resistance-associated mutations, as well as reduced replicative capacity, fitness, and infectivity of resistant virus strains (1, 3, 5, 11, 13, 18, 20-22, 26, 32, 34, 39).Mutations at position 88 of PR cause a reduction of susceptibility to the PR inhibitors nelfinavir, BMS-232632, and SC-55389A (9, 23, 36). N88S/D mutations emerged in protease sequences derived from 20% of individuals who had failed a therapy regimen containing nelfinavir, though the two mutations occured in different sequence contexts (23). A subset of virus strains with reduced susceptibility to nelfinavir was subsequently shown to have a 3-to 12-fold increase in susceptibility to amprenavir, another PR inhibitor (40). The amprenavir hypersusceptibility was...

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Section: Discussionsupporting

confidence: 84%

Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly

Resch¹,

Ziermann

Parkin

et al. 2002

J Virol

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“…The negative correlation between D30N and the other primary protease inhibitor resistance mutations may reflect the fact that D30N decreases protease fitness without contributing resistance to any protease inhibitor other than nelfinavir (6,12,18). Alternatively, enzymes containing D30N together with other primary mutations appear to have decreased activity (28).…”

Section: Discussionmentioning

confidence: 99%

Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments

Wu¹,

Schiffer

Gonzales

et al. 2003

J Virol

216

262

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“…Resistance-related mutations have been conventionally classified as primary or secondary based on their effect on drug susceptibility. While primary mutations reduce drug susceptibility, secondary mutations do not confer resistance by themselves but can enhance the replicative fitness and resistance levels of viruses with primary mutations (9). Of the mutations selected by AZT, T215Y/F and K70R are generally considered primary, whereas D67N, L210W, or K219Q/E are considered secondary.…”

mentioning

confidence: 99%

“…Despite the accumulation of secondary mutations, drug-resistant viruses generally display a reduced replication capacity compared to WT viruses (7,9,27). Therefore, it was not unexpected to observe that transmitted drug-resistant mutants gradually lose resistance mutations that confer high fitness costs as they evolve to more fit viruses (2,8,37).…”

mentioning

confidence: 99%

Transmitted Human Immunodeficiency Virus Type 1 Carrying the D67N or K219Q/E Mutation Evolves Rapidly to Zidovudine Resistance In Vitro and Shows a High Replicative Fitness in the Presence of Zidovudine

Garcı́a-Lerma¹,

MacInnes²,

Bennett³

et al. 2004

J Virol

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Drug-naive patients infected with drug-resistant human immunodeficiency virus type 1 (HIV-1) who initiate antiretroviral therapy show a shorter time to virologic failure than patients infected with wild-type (WT) viruses. Resistance-related HIV genotypes not commonly seen in treated patients, which likely result from reversion or loss of primary resistance mutations, have also been recognized in drug-naive persons. Little work has been done to characterize the patterns of mutations in these viruses and the frequency of occurrence, their association with phenotypic resistance, and their effect on fitness and evolution of resistance. Through the analysis of resistance mutations in 1082 newly diagnosed antiretroviral-naive persons from the United States, we found that 35 of 48 (72.9%) persons infected with HIV-1 containing thymidine analog mutations (TAMs) had viruses that lacked a primary mutation (T215Y/F, K70R, or Q151M). Of these viruses, 9 (25.7%) had only secondary TAMs (D67N, K219Q, M41L, or F77L), and all were found to be sensitive to zidovudine (AZT) and other drugs. To assess the impact of secondary TAMs on the evolution of AZT resistance, we generated recombinant viruses from cloned plasma-derived reverse transcriptase sequences. Two viruses had D67N, three had D67N and K219Q/E, and three were WT. Four site-directed mutants with D67N, K219Q, K219E, and D67N/K219Q were also made in HIV-1 HXB2 . In vitro selection of AZT resistance showed that viruses with D67N and/or K219Q/E acquired AZT resistance mutations more rapidly than WT viruses (36 days compared to 54 days; P ‫؍‬ 0.003). To investigate the factors associated with the rapid selection of AZT mutations in these viruses, we evaluated fitness differences among HXB2 WT and HXB2 D67N or HXB2 D67N/K219Q in the presence of AZT. Both HXB2 D67N/K219Q and HXB2 D67N were more fit than HXB2 WT in the presence of either low or high AZT concentrations, likely reflecting low-level resistance to AZT that is not detectable by phenotypic testing. In the absence of AZT, the fitness cost conferred by D67N or K219Q was modest. Our results demonstrate that viruses with unique patterns of TAMs, including D67N and/or K219Q/E, are commonly found among newly diagnosed persons and illustrate the expanding diversity of revertant viruses in this population. The modest fitness cost conferred by D67N and K219Q supports persistence of these mutants in the untreated population and highlights the potential for secondary transmission. The faster evolution of these mutants toward AZT resistance is consistent with the higher viral fitness in the presence of AZT and shows that these viruses are phenotypically different from WT HIV-1. Our study emphasizes the need for clinical studies to better define the impact of these mutants on treatment responses and evolution of resistance.

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Replicative fitness in vivo of HIV‐1 variants with multiple drug resistance‐associated mutations

Cited by 90 publications

References 23 publications

Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly

Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly

Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments

Transmitted Human Immunodeficiency Virus Type 1 Carrying the D67N or K219Q/E Mutation Evolves Rapidly to Zidovudine Resistance In Vitro and Shows a High Replicative Fitness in the Presence of Zidovudine

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