Fidelity of classwide-resistant HIV-2 reverse transcriptase and differential contribution of K65R to the accuracy of HIV-1 and HIV-2 reverse transcriptases.
Introduction: L74V, E89G, V111I, S215Y, L74V/S215Y and E89G/S215Y), whose effects were evaluated for a small subset of misincorporations or mispairs using nucleotide discrimination assays.
Altered error specificity of RNase H-deficient HIV-1 reverse transcriptases during DNA-dependent DNA synthesis.
Discussion: E89G RT and RNase H-deficient mutants share an increased fidelity of mispair extension in comparison with the wild-type RT.
Discussion: Frameshift errors made by the E89G mutant accumulated at well-known hotspots such as the
Discussion: Interestingly, the substitution of Gly for Glu89 did not have a major effect on the overall fidelity of the HIV-1HXB2 RT as determined in forward mutation assays, but as observed with the HIV-1 group O RNase H-deficient mutants, the E89G RT showed a relatively high tendency to introduce frameshift errors (both run and non-run-associated), and a higher accuracy for base substitutions in comparison with the wild-type RT.
Lys66 residue as a determinant of high mismatch extension and misinsertion rates of HIV-1 reverse transcriptase.
Discussion: Several substitutions at residues that do not directly line the active site, but yet impinge upon it via interaction with template or primer, such as Met230Ile (in the primer grip) and Glu89Gly (at -2 position on the template) have also been shown to bring about increases in fidelity.
The glutamine side chain at position 91 on the beta5a-beta5b loop of human immunodeficiency virus type 1 reverse transcriptase is required for stabilizing the dNTP binding pocket.
Result: These results suggest that the substitution has affected the enzyme activity in a manner similar to that affected by E89G or Y183F alteration.
Discussion: However, the E89G mutant enzyme has been shown to have higher processivity, which probably compensates for its decreased forward synthesis, a consequence of decreased polymerase activity and increased fidelity.
Discussion: It has been reported that mutation E89G is resistant to PFA, along with ddTTP, ddCTP, ddATP, ddGTP, AZTTP, and 3TCTP.
Discussion: These enzyme characteristics are similar to those of the E89G mutant enzyme that has been isolated from HIV-1 infected cell culture.
HIV-1 reverse transcriptase mutations that confer decreased in vitro susceptibility to anti-RT DNA aptamer RT1t49 confer cross resistance to other anti-RT aptamers but not to standard RT inhibitors.
Result: In contrast, mutations shown to confer resistance to multiple NRTIs, including Table: E89G
Discussion: However, both E89G, which rarely occurs among clinical isolates as a primary mutation and the more commonly encountered K65R, both display a modest level of resistance to RT1t49 (3- to 5-fold).
Discussion: The K65R and E89G mutants have been reported to display reductions of 50% and 32% in their dissociation constants [,196,215].
Discussion: The above observation, however, was tempered by the fact that some of the NRTI-resistance mutations, such as E89G and K65R conferred a significant degree of resistance to RT1t49 (3 to 5-fold).
Antiretroviral drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase increase template-switching frequency.
Abstract: Several mutations associated with resistance to antiviral nucleoside analogs (K65R, L74V, E89G, Q151N, and M184I) dramatically increased RT template-switching frequencies by two- to sixfold in a single replication cycle.
Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys.
PMID: 11679914
2001
The Journal of infectious diseases
Abstract: Five of the infected monkeys maintained high virus loads; the sixth, which was infected with the E89G mutant strain, maintained viremia at a level below the limit of detection.
Abstract: Sequence analysis demonstrated substantial reversion of the E89G mutation in the animals with progressive infection and preservation of this mutation in the animal with controlled infection.
Abstract: Six macaques were inoculated with wild-type or mutated derivatives (E89G or E89G and M184V) of simian immunodeficiency virus macaque (SIVmac) 239.
Abstract: These results demonstrate that the E89G mutation has a significant negative impact on SIVmac fitness, whereas SIVmac bearing M184V achieved high, sustained virus loads, perhaps with a compen
Fidelity analysis of HIV-1 reverse transcriptase mutants with an altered amino-acid sequence at residues Leu74, Glu89, Tyr115, Tyr183 and Met184.
PMID: 10785387
2000
European journal of biochemistry
Abstract: For the 3TC-resistant Met184-->Val RT mutant an almost wild-type level of overall mutation frequency was observed, while the foscarnet-resistant RTs harbouring the Glu89-->Gly mutation showed only a twofold decrease in mutation frequency.
Abstract: We found that the reported higher fidelity of nucleotide incorporation by the Met184-->Val and Glu89-->Gly mutant reverse transcriptases (RTs) was not reflected in a substantial increase in the overall fidelity for these RT mutants.
Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys.
Abstract: The relative efficiencies with which the wild type, E89G, M184V and M184V/E89G HIV-
Abstract: These results suggest that amino acid substitutions that increase the fidelity of dNTP insertion do not necessarily increase misextension fidelity, and that the decreased misextension fidelity may counterbalance the increases in misinsertion fidelity observed for E89G and M184V RTs.
Abstract: Two nucleoside analog resistance mutations in HIV-1 reverse transcriptase (RT), E89G and M184V, were previously shown to increase the dNTP insertion fidelity of HIV-1 RT.
Effects of reverse-transcriptase mutations M184V and E89G on simian immunodeficiency virus in Rhesus monkeys.
PMID: 9705331
1998
The Journal of biological chemistry
Abstract: Thus, the E89G substitution is a dominant determinant in regard to each of the koff values from
Abstract: To characterize further these substitutions, we performed processivity assays alongside an analysis of pausing profiles with wild-type (wt) RT and recombinant RTs containing substitutions at E89G, M184V, or both.
Abstract: Viruses containing the E89G mutation synthesized longer strand DNA products than either wt viruses or viruses containing only the M184V mutation in endogenous RT assays.
Abstract: We now show that E89G RT has higher processivity than wt enzyme as well as a different pattern of pausing sites.
HIV mutation literature information.
PMID: 
2017
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