Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy

Precious, Heather M.; Günthard, Huldrych F.; Wong, Joseph K.; D’Aquila, Richard T.; Johnson, Victoria A.; Kuritzkes, Daniel R.; Richman, Douglas D.; Brown, Andrew

doi:10.1097/00002030-200001070-00004

Cited by 152 publications

(17 citation statements)

References 23 publications

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“…The results of several studies point to the potential significance of mutations at codons 44 and 118 in patients treated with nucleoside RT inhibitors (2,5,16,17). Our finding that the 44D/E and 118I mutations were more common in viruses from ZDV-and 3TC-treated patients is consistent with these results.…”

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confidence: 89%

Phenotypic and Genotypic Analysis of Biologically Cloned Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Zidovudine and Lamivudine

Stoeckli

MaWhinney

et al. 2002

Antimicrob Agents Chemother

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Mutations at reverse transcriptase codons 44, 118, 207, and 208 were significantly correlated with reduced zidovudine susceptibility in biologically cloned human immunodeficiency virus type 1 (HIV-1) isolates. Sequences from the Stanford HIV RT and Protease Sequence Database showed that these mutations were more common in HIV-1 isolates from patients treated with zidovudine and lamivudine than in patients not treated with these drugs.The combination of zidovudine (ZDV) and lamivudine (3TC) remains effective at inhibiting the replication of human immunodeficiency virus type 1 (HIV-1) despite the rapid emergence of 3TC resistance. This effectiveness is based in part on the interaction between the 3TC resistance mutation at reverse transcriptase (RT) codon 184 and ZDV resistance mutations. Introduction of the M184V substitution into strains carrying ZDV resistance mutations results in reversal of ZDV resistance (18), whereas coadministration of ZDV and 3TC results in delayed emergence of ZDV resistance mutations (9, 11). However, dually resistant isolates have been recovered from patients failing ZDV-3TC therapy (3,14).Mutations at both the 5Ј and 3Ј ends of the RT gene modulate expression of dual resistance [15; S. D. Kemp and S. Bloor, Antivir. Ther. 2(Suppl. 5):21-22, abstr. 11, 1997]. In addition, a G333E substitution promotes dual resistance in some, but not all, strains that harbor the classical ZDV and 3TC resistance mutations (8). To investigate further the genetic basis of dual resistance to ZDV and 3TC, we conducted a comprehensive clonal analysis of the phenotypic and genotypic characteristics of HIV-1 isolates from patients on prolonged treatment with these drugs.Isolation and characterization of biological clones. Primary HIV-1 isolates resistant to ZDV and 3TC were cultured on peripheral blood mononuclear cells at limiting dilutions to generate independent biological clones (3). Susceptibilities of the clonal isolates to ZDV and 3TC were determined as described previously (6, 7). Resistance to ZDV was defined as intermediate (ZDV i ; 50% inhibitory concentration [IC 50 ] Ն 0.1 M and Ͻ 1.0 M) or high level (ZDV r ; IC 50 Ն 1.0 M) (7); resistance to 3TC (3TC r ) was defined as an IC 50 of Ն1.0 M (10). Thirty biological clones were generated from 10 ZDV r 3TC r and 4 ZDV i 3TC r primary HIV-1 isolates, which were originally obtained from nine patients (3). The following phenotypes were observed: ZDV r 3TC r (eight clones), ZDV i

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confidence: 89%

Phenotypic and Genotypic Analysis of Biologically Cloned Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Zidovudine and Lamivudine

Stoeckli

MaWhinney

et al. 2002

Antimicrob Agents Chemother

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“…It is also possible that differences in the intracellular concentrations of nucleoside analog triphosphates and the deoxynucleoside triphosphate pool result in different selective pressures on RT (6). In addition, viral subtype and polymorphisms in RT that are not associated with drug resistance could influence the emergence of specific TAMs through mutational interactions (32).…”

Section: Vol 80 2006 Fitness Of Zidovudine-resistant Hiv-1 7023mentioning

confidence: 99%

Fitness Comparison of Thymidine Analog Resistance Pathways in Human Immunodeficiency Virus Type 1

Giguel

Hatano

et al. 2006

J Virol

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Resistance to zidovudine (ZDV) results from thymidine analog resistance mutations (TAMs) at human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) codons 41, 67, 70, 210, 215, and 219. Two mutations are possible at codon 215: Y or F. Whereas T215Y occurs alone or with M41L and L210W (TAM-1 pattern), T215F rarely occurs with these mutations or by itself; it is found instead with D67N, K70R, and K219Q (TAM-2 pattern). The L210W mutation most often occurs with M41L and T215Y and rarely occurs with the T215F or TAM-2 mutation. To explain these associations, TAMs were introduced into HIV-1 Hxb2 by site-directed mutagenesis and expressed in recombinant viruses. Viral replication kinetics, relative fitness, and infectivity were tested in the absence or presence of ZDV. Viruses carrying the 215Y mutation showed faster replication kinetics and greater relative fitness than did T215F mutants in the absence or presence of ZDV. In addition, T215Y mutants showed greater infectivity than did wild-type HIV-1 over a range of ZDV concentrations, but T215F mutants had only a modest advantage over the wild-type virus. Whereas introduction of L210W improved the relative fitness of an M41L/T215Y mutant in the presence of ZDV, introduction of this mutation into a D67N/K70R/K219Q background resulted in decreased relative fitness in the presence or absence of drug. By contrast, introduction of T215F into the D67N/K70R/K219Q background increased viral fitness in the presence of ZDV. These results help explain why T215Y but not T215F usually emerges as the first major TAM, as well as the clustering of L210W with TAM-1 mutations and T215F with TAM-2 mutations.

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“…The clinical benefits of antiretroviral treatment are limited by the selection of drug-resistant human immunodeficiency virus type 1 (HIV-1) strains during therapy (38). A recent U.S. survey reported that up to 70% of patients with detectable plasma viremia harbor drug-resistant viral variants (D. Richman, S. Bozzette, S. Morton, S. Chien, T. Wrin, K. Dawson, and N. Hellmann, Abstr.…”

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confidence: 99%

Infectivity and Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 Variants Isolated during Primary Infection

Simon

Padte

Murray

et al. 2003

J Virol

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It is believed that replication capacity is an important determinant of human immunodeficiency virus type 1 (HIV-1) pathogenicity and transmissibility. To explore this, we conducted a comprehensive analysis of the replication properties of nine drug-resistant and nine drug-susceptible viral isolates derived from patients with primary HIV-1 infection. Viral isolates were tested for single-cycle infectivity in the GHOST cell line. The infectivity of isolates carrying resistance-associated mutations was significantly higher than that of drugsusceptible isolates. Additionally, the growth kinetics of these isolates were determined in CD4 ؉ T lymphocytes. Drug-resistant isolates replicated as well as drug-susceptible viruses. Insertion of the resistanceconferring regions into an NL4-3-based molecular background resulted in chimeras that displayed a modest but significant reduction in replication capacity compared to the drug-susceptible chimeric viruses. Of note, two multidrug-resistant isolates and one protease inhibitor-resistant isolate displayed higher rates of infectivity and growth kinetics than the other drug-resistant or drug-susceptible isolates. These distinct replicative features, however, were not seen in the corresponding chimeras, indicating that changes within the C-terminal region of Gag as well as within the protease and reverse transcriptase genes contribute to but are not sufficient for the level of compensatory adaptation observed. These findings suggest that some drug-resistant viruses isolated during primary infection possess unique adaptive changes that allow for both high viral replication capacity and resistance to one or more classes of antiretroviral drugs. Further studies are needed to elucidate the precise regions that are essential for these characteristics.

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Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy

Cited by 152 publications

References 23 publications

Phenotypic and Genotypic Analysis of Biologically Cloned Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Zidovudine and Lamivudine

Phenotypic and Genotypic Analysis of Biologically Cloned Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Zidovudine and Lamivudine

Fitness Comparison of Thymidine Analog Resistance Pathways in Human Immunodeficiency Virus Type 1

Infectivity and Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 Variants Isolated during Primary Infection

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