Combination Therapy with Zidovudine and Didanosine Selects for Drug-Resistant Human Immunodeficiency Virus Type 1 Strains with Unique Patterns of pol Gene Mutations

Shafer, Robert W.; Kozal, Michael J.; Winters, Mark A.; Iversen, Astrid K. N.; Katzenstein, David; Ragni, Margaret V.; Meyer, William A.; Gupta, Phalquni; Rasheed, Suraiya; Coombs, Robert W.; Katzman, Michael; Fiscus, Susan A.; Merigan, Thomas C.

doi:10.1093/infdis/169.4.722

Cited by 192 publications

(132 citation statements)

References 18 publications

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“…The sequences from two of the five isolates have previously been studied and were consistent with sequence results obtained in this study (Table 1) [10,14,18].…”

Section: Characterization Of Viral Strainssupporting

confidence: 88%

Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Palmer

Shafer

Merigan

1999

AIDS

114

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Objectives-To assess the in-vitro drug susceptibility of a panel of five well-characterized drugresistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors.Methods-Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point.Results-These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound.Conclusions-It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.

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“…The sequences from two of the five isolates have previously been studied and were consistent with sequence results obtained in this study (Table 1) [10,14,18].…”

Section: Characterization Of Viral Strainssupporting

confidence: 88%

Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Palmer

Shafer

Merigan

1999

AIDS

114

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“…1, region III). A62V, V75I, and F77L are associated with Q151M in a multidrug-resistant complex (16), and, as previously discussed, V75T causes slight resistance to D4T (46). Besides abacavir, L74V has been associated with resistance to ddI and ddC (18,45).…”

Section: Role For the Hydrophobic Nature Of Cbvtp's Ribose Ring Inmentioning

confidence: 65%

“…Distinct mutations occur in the presence of different NRTIs, and their temporal occurrence is often predictable (13)(14)(15)(16)(17)(18). Initial mutations are often responsible for resistance to the compound, whereas later mutations increase the fitness of the mutant virus (19).…”

Section: Compounds Currently Approved By the Food And Drug Administramentioning

confidence: 99%

“…2) (41) and a subset of mutants found in an in vitro drug selection study (17). Conclusions were further tested using a clinically relevant multidrug-resistant mutant (Q151M (16)) and an AZT-resistant mutant (RT AZTR , D67N/K70R/T215Y/ K219Q (14,15)). Our study looked at both incorporation and removal (by PP i and ATP) along with other biochemical properties of these mutants.…”

Section: Compounds Currently Approved By the Food And Drug Administramentioning

confidence: 99%

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Mechanistic Studies to Understand the Progressive Development of Resistance in Human Immunodeficiency Virus Type 1 Reverse Transcriptase to Abacavir

Ray

Basavapathruni

Anderson

2002

Journal of Biological Chemistry

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Abacavir has been shown to select for multiple resistant mutations in the human immunodeficiency type 1 (HIV-1) pol gene. In an attempt to understand the molecular mechanism of resistance in response to abacavir, and nucleoside analogs in general, a set of reverse transcriptase mutants were studied to evaluate their kinetics of nucleotide incorporation and removal. It was found that, similar to the multidrug-resistant mutant reverse transcriptase (RT) Q151M, the mutations L74V, M184V, and a triple mutant containing L74V/Y115F/M184V all caused increased selectivity for dGTP over the active metabolite of abacavir (carbovir triphosphate). However, the magnitude of resistance observed in cell culture to abacavir in previous studies was less than that observed to other compounds. Our mechanistic studies suggest that this may be due to carbovir triphosphate decreasing the overall effect on its efficiency of incorporation by forming strong hydrophobic interactions in the RT active site. Unlike RT AZTR , no increase in the rate of ATP-or PP imediated chain terminator removal relative to RT WT could be detected for any of the mutants. However, marked decreases in the steady-state rate may serve as a mechanism for increased removal of a chain-terminating carbovir monophosphate by increasing the time spent at the primer terminus for some of the mutants studied. The triple mutant showed no advantage in selectivity over RT M184V and was severely impaired in its ability to remove a chain terminator, giving no kinetic basis for its increased resistance in a cellular system. Biochemical properties including percentage of active sites, fidelity, and processivity may suggest that the triple mutant's increased resistance to abacavir in cell culture is perhaps due to a fitness advantage, although further cellular studies are needed to verify this hypothesis. These data serve to further the understanding of how mutations in RT confer resistance to nucleoside analogs.

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“…Virus resistance to medication (Shafer et al 1994, Larder & Kemp 1989, D'Aquila et al 2002 has been a major challenge to the long term success of therapy. However, genotypic information may orient the rescue ARV therapy (Clevenbergh et al 2000).…”

mentioning

confidence: 99%

Antiretroviral resistance mutations in human immunodeficiency virus type 1 infected patients enrolled in genotype testing at the Central Public Health Laboratory, São Paulo, Brazil: preliminary results

Rodrigues

Vazquez

Colares

et al. 2005

Mem. Inst. Oswaldo Cruz

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Combination Therapy with Zidovudine and Didanosine Selects for Drug-Resistant Human Immunodeficiency Virus Type 1 Strains with Unique Patterns of pol Gene Mutations

Cited by 192 publications

References 18 publications

Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Mechanistic Studies to Understand the Progressive Development of Resistance in Human Immunodeficiency Virus Type 1 Reverse Transcriptase to Abacavir

Antiretroviral resistance mutations in human immunodeficiency virus type 1 infected patients enrolled in genotype testing at the Central Public Health Laboratory, São Paulo, Brazil: preliminary results

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