scholarly journals An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3'-azido-3'-deoxythymidine.

1996 ◽  
Vol 70 (11) ◽  
pp. 8010-8018 ◽  
Author(s):  
D J Hooker ◽  
G Tachedjian ◽  
A E Solomon ◽  
A D Gurusinghe ◽  
S Land ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
High Level ◽  
Level Resistance

scholarly journals High-Level Resistance to 3′-Azido-3′-Deoxythimidine due to a Deletion in the Reverse Transcriptase Gene of Human Immunodeficiency Virus Type 1

2000 ◽  
Vol 74 (2) ◽  
pp. 1023-1028 ◽  
Author(s):  
Tomozumi Imamichi ◽  
Tanima Sinha ◽  
Hiromi Imamichi ◽  
Yi-Ming Zhang ◽  
Julie A. Metcalf ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Azt Resistance ◽  
High Level ◽  
Level Resistance

ABSTRACT A variant of human immunodeficiency virus type 1 (HIV-1) possessing a deletion in the reverse transcriptase (RT) gene at codon 67 was identified in a patient who had failed combination antiretroviral therapy. This deletion initially emerged under the selective pressure of combination therapy with 3′-azido-3′-deoxythymidine (AZT) plus 2′,3′-dideoxyinosine. It has persisted for more than 3 years in association with the accumulation of a variety of other well-described drug resistance mutations and an uncharacterized mutation at RT codon 69 (T69G). Phenotypic studies demonstrated that the codon 67 deletion by itself had little effect on AZT sensitivity. However, in the context of the T69G mutation and three other mutations known to be associated with AZT resistance (K70R, T215F, and K219Q), this deletion led to a increase in AZT resistance from 8.5-fold to 445-fold. A further increase in resistance (up to 1,813-fold) was observed when two mutations associated with nonnucleoside RT inhibitor resistance (K103N and L74I) were added to the deletion T69G K70R T215F K219Q construct. Hence, these results establish that a deletion at RT codon 67 may be selected for in the presence of antiretroviral therapy and may lead to high-level resistance to AZT.

scholarly journals Coresistance to Zidovudine and Foscarnet Is Associated with Multiple Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase

1998 ◽  
Vol 42 (11) ◽  
pp. 3038-3043 ◽  
Author(s):  
Gilda Tachedjian ◽  
Martyn French ◽  
John Mills
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Evolutionary Path ◽  
In Vivo Selection ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) isolates obtained from a patient with AIDS were assessed for coresistance to foscarnet and zidovudine. An HIV-1 strain (AP20) coresistant to foscarnet and zidovudine was isolated after 20 months of continuous combination therapy. The reverse transcriptase (RT) gene of AP20 had 41 substitutions which were different from the HXB2-D sequence and 9 that were different from the sequence of its foscarnet-sensitive, zidovudine-resistant progenitor virus (AP6). Six of these mutations were nonpolymorphic (T39A, V108I, K166R, K219R, K223Q, and L228R). Both strains had the conventional mutations mediating zidovudine resistance. In vivo selection may result in HIV-1 strains that are coresistant to foscarnet and zidovudine, but coresistance appears to require a complex evolutionary path and multiple RT mutations.

scholarly journals A recombinant retroviral system for rapid in vivo analysis of human immunodeficiency virus type 1 susceptibility to reverse transcriptase inhibitors.

1997 ◽  
Vol 41 (12) ◽  
pp. 2781-2785 ◽  
Author(s):  
C Shi ◽  
J W Mellors
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Susceptibility ◽  
Phenotypic Resistance ◽  
Immunodeficiency Virus ◽  
Hiv 1

We have developed a new recombinant retroviral system in which a library of infectious molecular clones of human immunodeficiency virus type 1 (HIV-1) is constructed with reverse transcriptase (RT) genes derived from viral RNA sequences in plasma. HIV-1 RT is amplified from plasma HIV-1 RNA by nested RT-PCR and cloned into a RT-defective HIV-1 proviral vector (xxLAI-np), generating 10(3) to 10(4) recombinant proviral clones from each reaction. The bulk cloning products or individual molecular clones are transfected into MT-2 cells to generate infectious virus. The resultant viruses are assayed for drug susceptibility in CD4+ cell lines to determine either the dominant phenotype of the recombinant virus mixture or the phenotypes of the individual viral clones. DNA sequencing of the cloned RT genes can identify mutations associated with phenotypic resistance of clonal mixtures or individual clones. This method can be used to rapidly detect the in vivo emergence of HIV-1 quasispecies resistant to RT inhibitors.

scholarly journals Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

2005 ◽  
Vol 79 (16) ◽  
pp. 10638-10649 ◽  
Author(s):  
Wolfgang Resch ◽  
Neil Parkin ◽  
Terri Watkins ◽  
Janera Harris ◽  
Ronald Swanstrom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Replication Capacity ◽  
Immunodeficiency Virus ◽  
Evolution Of Resistance

ABSTRACT We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.

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