Insertion of two animo acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs

Jong, J J de; Goudsmit, Jaap; Lukashov, Vladimir V.; Hillebrand, Merle; Baan, Elly; Huismans, Raymond; Danner, Sven A.; Veen, J; Wolf, Frank de; Jurriaans, Suzanne

doi:10.1097/00002030-199901140-00010

Cited by 98 publications

(78 citation statements)

References 13 publications

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“…As similar types of insertion mutations were reported in the RT gene (6,20,21) pol type during the therapy in all cases were obtained. Taken together, we suggest that this type of insertion in the p6 gag and p6 pol genes enhances the proliferation and/or the survival of the HIV-1 variant in the presence of antiretroviral drugs.…”

Section: Characteristics Of the Insertion Mutations Detected In The P6supporting

confidence: 80%

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy

Ibe

Shibata

Utsumi

et al. 2003

Microbiology and Immunology

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We detected several types of human immunodeficiency virus type 1 (HIV‐1) variants with an insertion mutation in the p6gag and p6pol genes in eight of twenty‐two (36.4%) patients who possessed drug‐resistant viruses under highly active antiretroviral therapy (HAART). It was characteristic that a conserved proline‐rich motif “PTAPP” in the N‐terminus of p6gag protein was completely or partially duplicated in all cases. Five among the eight cases were retrospectively investigated in terms of the occurrence of dynamic change in the gag gene between the inserted and wild‐type HIV‐1 in the course of HAART. The longitudinal analysis revealed the following: 1) The inserted‐type viruses were selected over the wild‐type during HAART in three cases in which the both types coexisted in the beginning of the therapy. 2) In two cases in which the inserted‐type HIV‐1 alone was detected before the beginning of HAART, the inserted‐type HIV‐1 alone was continuously detected during the therapy. The inserted‐type HIV‐1 was also detected in four of thirty‐nine (10.3%) therapy‐naive patients. However, the frequency of inserted‐type HIV‐1 detection in the HAART‐receiving patients is significantly higher than that in the therapy‐naive patients (P=0.02). These results suggest that this type of insertion mutation is a polymorphism of the p6gag and p6pol genes, however, it consequently gave an advantage on proliferation and/or survival of the HIV‐1 variant under the presence of antiretroviral drugs.

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Section: Characteristics Of the Insertion Mutations Detected In The P6supporting

confidence: 80%

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy

Ibe

Shibata

Utsumi

et al. 2003

Microbiology and Immunology

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“…This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2,17,29). The K65R mutation appears infrequently during the course of treatment with dideoxyinosine (ddI; didanosine) and dideoxycytosine and confers concomitant low-level 3TC resistance (4,5).…”

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confidence: 94%

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

Hertogs¹,

Bloor²,

Vroey³

et al. 2000

Antimicrob Agents Chemother

107

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We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pattern associated with phenotypic resistance to lamivudine (3TC) in the absence of the characteristic replacement of methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4-and 50-fold) to 3TC in a subset of isolates that did not harbor the M184V mutation. Mutational cluster analysis and comparison with the phenotypic data revealed a significant correlation between moderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by isoleucine at residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC resistance was confirmed by site-directed mutagenesis experiments. These data support the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of particular mutations may affect susceptibility to drugs that have never been part of a particular regimen.The emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is almost always observed during the course of treatment of patients with antiretroviral drugs (3, 10, 14-16, 18, 21, 27 Strategies, abstr. 19, p. 15, 1998). The mutational profile of the resistant viruses generally is characteristic for the particular drug(s) taken. For example, mutations at codons 41, 67, 70, 210, 215, and 219 of reverse transcriptase (RT) typically confer resistance to zidovudine (ZDV) (6,12,13,27). Similarly, mutation M184V in RT has been shown to be specifically associated with high-level (Ն50-fold) phenotypic resistance to lamivudine (3TC) (1,22,28). No "specific" mutation(s) associated with moderate levels of phenotypic resistance (4-to Ͻ50-fold) to 3TC has been described before. Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29). The K65R mutation appears infrequently during the course of tr...

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“…Another MDR complex of RT mutations is the "fingers insertion" complex that includes an insertion of two residues at the fingers subdomain of the p66 subunit of RT in the presence of AZT resistance mutations, e.g., M41L and T215Y (M41L/T69SSG/T215Y). This complex can emerge during combination treatment that includes NRTIs (10,41) and confers resistance to multiple drugs by enhancing the excision reaction that causes resistance by unblocking NRTI-terminated primers (40). G333E or G333D polymorphisms with thymidine analogue-associated mutations (TAMs) and M184V have also been reported to facilitate moderate resistance to at least two NRTIs, AZT and lamivudine (3TC) (7,22).…”

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confidence: 99%

Amino Acid Mutation N348I in the Connection Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confers Multiclass Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

Hachiya

Kodama

Sarafianos

et al. 2008

J Virol

107

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We identified clinical isolates with phenotypic resistance to nevirapine (NVP) in the absence of known nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. This resistance is caused by N348I, a mutation at the connection subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Virologic analysis showed that N348I conferred multiclass resistance to NNRTIs (NVP and delavirdine) and to nucleoside reverse transcriptase inhibitors (zidovudine [AZT] and didanosine [ddI]). N348I impaired HIV-1 replication in a cell-type-dependent manner. Acquisition of N348I was frequently observed in AZTand/or ddI-containing therapy (12.5%; n ‫؍‬ 48; P < 0.0001) and was accompanied with thymidine analogueassociated mutations, e.g., T215Y (n ‫؍‬ 5/6) and the lamivudine resistance mutation M184V (n ‫؍‬ 1/6) in a Japanese cohort. Molecular modeling analysis shows that residue 348 is proximal to the NNRTI-binding pocket and to a flexible hinge region at the base of the p66 thumb that may be affected by the N348I mutation. Our results further highlight the role of connection subdomain residues in drug resistance.

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Insertion of two animo acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs

Cited by 98 publications

References 13 publications

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

Amino Acid Mutation N348I in the Connection Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confers Multiclass Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

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Insertion of two animo acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs

Cited by 98 publications

References 13 publications

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6gag and p6pol Genes under Highly Active Antiretroviral Therapy

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6gag and p6pol Genes under Highly Active Antiretroviral Therapy

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

Amino Acid Mutation N348I in the Connection Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confers Multiclass Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

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Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy

Selection of Human Immunodeficiency Virus Type 1 Variants with an Insertion Mutation in the p6^gag and p6^pol Genes under Highly Active Antiretroviral Therapy