Identification of alternative amino acid substitutions in drug-resistant variants of the HIV-1 reverse transcriptase

AIDS ◽  
2006 ◽  
Vol 20 (11) ◽  
pp. 1515-1520 ◽  
Author(s):  
Ben Berkhout ◽  
Nicole KT Back ◽  
Anthony de Ronde ◽  
Suzanne Jurriaans ◽  
Margreet Bakker ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Amino Acid Substitutions ◽  
Drug Resistant ◽  
Alternative Amino Acid ◽  
Hiv 1

scholarly journals Effects of the Δ67 Complex of Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Nucleoside Analog Excision

2004 ◽  
Vol 78 (18) ◽  
pp. 9987-9997 ◽  
Author(s):  
Paul L. Boyer ◽  
Tomozumi Imamichi ◽  
Stefan G. Sarafianos ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Coding Region ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Long-term use of combination therapy against human immunodeficiency virus type (HIV-1) provides strong selective pressure on the virus, and HIV-1 variants that are resistant to multiple inhibitors have been isolated. HIV-1 variants containing amino acid substitutions within the coding region of HIV-1 reverse transcriptase (RT), such as the 3′-azido-3′-deoxythymidine (AZT)-resistant variant AZT-R (M41L/D67N/K70R/T215Y/K219Q) and a variant containing an insertion in the fingers domain (S69SGR70/T215Y), are resistant to the nucleoside RT inhibitor (NRTI) AZT because of an increase in the level of excision of AZT monophosphate (AZTMP) from the primer. While rare, variants have also been isolated which contain deletions in the RT coding region. One such virus, described by Imamichi et al. (J. Virol 74:10958-10964, 2000; J. Virol. 74:1023-1028, 2000; J. Virol. 75:3988-3992, 2001), contains numerous amino acid substitutions and a deletion of codon 67, which we have designated the Δ67 complex of mutations. We have expressed and purified HIV-1 RT containing these mutations. We compared the polymerase and pyrophosphorolysis (excision) activity of an RT with the Δ67 complex of mutations to wild-type RT and the two other AZT-resistant variants described above. All of the AZT-resistant variants we tested excise AZTMP and 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA [tenofovir]) from the end of a primer more efficiently than wild-type RT. Although the variant RTs excised d4TMP less efficiently than AZTMP and PMPA, they were able to excise d4TMP more efficiently than wild-type RT. HIV-1 RT containing the Δ67 complex of mutations was not able to excise as broad a range of NRTIs as the fingers insertion variant SSGR/T215Y, but it was able to polymerize efficiently with low concentrations of deoxynucleoside triphosphates and seems to be able to excise AZTMP and PMPA at lower ATP concentrations than AZT-R or SSGR/T215Y, suggesting that a virus containing the Δ67 complex of mutations would replicate reasonably well in quiescent cells, even in the presence of AZT.

S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1

1998 ◽  
Vol 42 (6) ◽  
pp. 1340-1345 ◽  
Author(s):  
Tamio Fujiwara ◽  
Akihiko Sato ◽  
Mohamed El-Farrash ◽  
Shigeru Miki ◽  
Kenji Abe ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Reverse Transcriptase Inhibitors ◽  
Human T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.

scholarly journals Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

2014 ◽  
Vol 59 (2) ◽  
pp. 960-971 ◽  
Author(s):  
Adriaan E. Basson ◽  
Soo-Yon Rhee ◽  
Chris M. Parry ◽  
Ziad El-Khatib ◽  
Salome Charalambous ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Resistance Testing ◽  
Amino Acid Substitutions ◽  
Subtype C ◽  
Nnrti Resistance ◽  
High Level ◽  
Hiv 1 ◽  
Phenotypic Susceptibility ◽  
Level Resistance

ABSTRACTThe objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in anin vitrosingle-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.

PASS-based approach to predict HIV-1 reverse transcriptase resistance

2017 ◽  
Vol 15 (02) ◽  
pp. 1650040 ◽  
Author(s):  
Olga Tarasova ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Open Data ◽  
Amino Acid Substitutions ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Hiv Drugs ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

scholarly journals Gln145Met/Leu Changes in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nucleoside and Nonnucleoside Analogs and Impair Virus Replication

2004 ◽  
Vol 48 (12) ◽  
pp. 4611-4617 ◽  
Author(s):  
Stefania Paolucci ◽  
Fausto Baldanti ◽  
Giovanni Maga ◽  
Reynel Cancio ◽  
Maurizio Zazzi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Multidrug Resistance ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Virus Replication ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The frequencies of multidrug resistance-associated mutations at codons 145, 151, and 69 of the human immunodeficiency virus (HIV) reverse transcriptase (RT) gene in strains from a group of 3,595 highly active antiretroviral therapy (HAART)-experienced patients were 0.22, 2.36, and 0.86%, respectively. Several amino acid substitutions different from the recently reported Gln145Met change (S. Paolucci, F. Baldanti, M. Tinelli, G. Maga, and G. Gerna, AIDS 17:924-927, 2003) were detected at position 145. Thus, amino acid substitutions selected at position 145 were introduced into the wild-type HIV type 1 (HIV-1) RT gene by site-directed mutagenesis, and recombinant HIV strains were assayed for their drug susceptibilities. Only Met and Leu substitutions at position 145 of the HIV-1 RT conferred multidrug resistance, while other amino acid changes did not. Lower levels of replication of the Gln145Met recombinant strain compared with those of both Gln151Met and wild-type recombinant strains were observed. In in vitro inhibition assays, expression and purification of the recombinant Gln145Met HIV-1 RT revealed a strong loss of catalytic efficiency of the mutated enzyme, as well as significant resistance to both zidovudine and efavirenz. Specific amino acid substitutions in the HIV RT nucleotide-binding pocket might affect both antiretroviral drug recognition and binding and decrease the level of virus replication, possibly by interfering with the enzyme activity. This finding may explain the lower frequency of Gln145Met/Leu mutations observed compared with the frequencies of Gln151Met/Leu mutations and the insertion at position 69 in HAART-experienced patients.

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