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

Paolucci, Stefania; Baldanti, Fausto; Maga, Giovanni; Cancio, Reynel; Zazzi, Maurizio; Zavattoni, Maurizio; Chiesa, A.; Spadari, Silvio; Gerna, Giuseppe

doi:10.1128/aac.48.12.4611-4617.2004

Cited by 18 publications

(13 citation statements)

References 29 publications

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“…Two previous reports have shown that two rare mutations, Q145M/L and Y181I, can confer cross-resistance to some NRTIs and NNRTIs (31,32). N348I appears to be the first reported high-prevalence amino acid mutation to confer resistance to multiple members of the NRTI and NNRTI families.…”

Section: Discussionmentioning

confidence: 99%

“…However, so far all reports of viruses that acquire resistance to members of both families of RT inhibitors describe variants with multiple mutations at several residues that confer either NRTI or NNRTI resistance. Recently, Paolucci et al reported that Q145M/L mutations confer cross-resistance to some NRTIs and NNRTIs (31,32). Similarly, an NNRTI resistance mutation, Y181I, also confers resistance to d4T at the enzyme level (2).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Based on the growing evidence for the existence of dual NRTI and NNRTI resistance (4,23,24,33,40,59), we have explored the mechanism by which mutations in RT can confer dual resistance. Here, we propose a new unifying mechanism for NNRTI resistance that explains the dual NRTI and NNRTI resistance conferred by mutations in the CN and RNase H of RT.…”

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Mechanism of Dual Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

Nikolenko

Delviks-Frankenberry

Pathak

2010

J Virol

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Recently, mutations in the connection subdomain (CN) and RNase H domain of HIV-1 reverse transcriptase (RT) were observed to exhibit dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). To elucidate the mechanism by which CN and RH mutations confer resistance to NNRTIs, we hypothesized that these mutations reduce RNase H cleavage and provide more time for the NNRTI to dissociate from the RT, resulting in the resumption of DNA synthesis and enhanced NNRTI resistance. We observed that the effect of the reduction in RNase H cleavage on NNRTI resistance is dependent upon the affinity of each NNRTI to the RT and further influenced by the presence of NNRTI-binding pocket (BP) mutants. D549N, Q475A, and Y501A mutants, which reduce RNase H cleavage, enhance resistance to nevirapine (NVP) and delavirdine (DLV), but not to efavirenz (EFV) and etravirine (ETR), consistent with their increase in affinity for RT. Combining the D549N mutant with NNRTI BP mutants further increases NNRTI resistance from 3- to 30-fold, supporting the role of NNRTI-RT affinity in our NNRTI resistance model. We also demonstrated that CNs from treatment-experienced patients, previously reported to enhance NRTI resistance, also reduce RNase H cleavage and enhance NNRTI resistance in the context of the patient RT pol domain or a wild-type pol domain. Together, these results confirm key predictions of our NNRTI resistance model and provide support for a unifying mechanism by which CN and RH mutations can exhibit dual NRTI and NNRTI resistance.

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“…Several studies have examined the prevalence of T69SϩXX inserts in cohorts from hospitals, clinics, and large reference laboratories (Table 2). Nine European studies (9,12,39,44,53,59,60,63,70) reported that an average of 1.6% of treated patients from clinical and hospital populations harbored T69SϩXX insert strains (range, 0.5% to 3.0%). Those studies evaluated patients through various time frames between 1996 and 1999.…”

Section: Rt Codon 69 Insertsmentioning

confidence: 99%

Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms

Winters

Merigan

2005

Antimicrob Agents Chemother

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

Cited by 18 publications

References 29 publications

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

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

A Novel Molecular Mechanism of Dual Resistance to Nucleoside and Nonnucleoside Reverse Transcriptase Inhibitors

Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms

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