Frequency and Treatment‐Related Predictors of Thymidine‐Analogue Mutation Patterns in HIV‐1 Isolates after Unsuccessful Antiretroviral Therapy

Luca, Andrea De; Giambenedetto, Simona Di; Romanò, Laura; Gonnelli, A.; Corsi, Paola; Baldari, Marco; Pietro, Massimo Di; Menzo, Stefano; Francisci, Daniela; Almi, P; Zazzi, Maurizio

doi:10.1086/502976

Cited by 24 publications

(22 citation statements)

References 12 publications

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“…However, geometrical constraints arising from the different conformation of the ZDVMP moiety in the binary complex could also affect the removal of the inhibitor. Our results also support previous reports showing that Tyr-208, Lys-211 and Phe-214 substitutions, despite lacking a direct effect on drug resistance per se, could increase ZDV resistance and cross-resistance when they appear in combination with amino acid substitutions of the TAM1 pathway (7,23,28).…”

Section: Discussionsupporting

confidence: 92%

“…This effect could be due to the fact that Leu-214 somehow inhibits the development of TAM1. It has been reported that this mutational profile confers higher phenotypic resistance to NRTIs than TAM2, thus providing a favorable effect on virological response (6,7,15,26). Moreover, our results suggest that Leu-214 not only influences viral fitness but could also play a direct role in drug susceptibility.…”

Section: Discussionsupporting

confidence: 54%

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Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

Puertas

Buzón

Artese

et al. 2009

J Virol

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A negative association between polymorphism Leu-214 and type-1 thymidine analogue mutations (TAM1) and a positive association with a clinically favorable virological response to thymidine analogue-based combination antiretroviral therapy have been described. In this study, the impact of Leu-214 on replication capacity and resistance to zidovudine (ZDV) of viruses containing TAM1 or TAM2 was determined. Leu-214 decreased the growth rate of viruses bearing Tyr-215, as well as their resistance to ZDV. This observation was confirmed by structural and molecular modeling data, suggesting a regulatory role for Leu-214 in the emergence and phenotypic resistance of TAM1.Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is responsible for the conversion of the viral single-stranded RNA genome into double-stranded DNA, prior to host-genome integration in target cells. RT has been widely considered a key target for combination antiretroviral therapy. Drugs targeting this viral enzyme include nucleoside analogues (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). One of the mechanisms contributing to decreased HIV susceptibility to NRTIs promotes the removal of the nucleoside analogue from the terminated DNA chain (22). The mutations responsible for this effect, thymidine analogue mutations (TAMs), emerge after long-term therapy with zidovudine (ZDV) and/or stavudine (d4T) and confer resistance to almost all clinically approved RT inhibitors. Two different TAM patterns have been defined: TAM1, including and TAM2,, and Gln/Glu-219. TAM1 is more prevalent and confers a higher degree of resistance to thymidine analogues (6,8,10,12,19,(32)(33)(34). To date, the factors driving one mutational pattern or another remain unclear, although the genomic background of the treatment-naive viral population, host factors such as HLA genotype (16), and stochastic effects could be involved.Leu-214 is a natural polymorphism in the RT coding region, and it is present in ca. 10 to 20% of antiretroviral treatment (ART)-naive and ART-experienced patients carrying any of the major HIV-1 subtypes A, B, or C (3, 4; http://www.hiv.lanl .gov/). A negative association between Leu-214 and the TAM1 pattern and a positive association with the TAM2 pattern have been observed (29). Moreover, it has recently been demonstrated the association of the Leu-214 with a favorable virological response to thymidine analogue-containing ART (3). These data suggest that Leu-214 may regulate divergent resistance pathways by affecting viral fitness and/or drug susceptibility. However, experimental evidence supporting these observations has not yet been reported. The aim of the present study was to compare the in vitro growth rate and relative viral fitness of HIV-1 recombinant mutants containing the Leu-214 polymorphism in RT containing TAM1 or TAM2 patterns, in both the absence and the presence of ZDV. A preliminary structural analysis was also performed in order to explain the putative role of this polymorphism in the RT replicative capacity at the ...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 54%

Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

Puertas

Buzón

Artese

et al. 2009

J Virol

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“…TAMs are common in low income countries in which the fixed-dose combinations containing thymidine analogues are the mainstay of therapy (Ross et al, 2001). TAMs are also common in HIV-1 isolates from patients who began therapy in the pre-highly active antiretroviral therapy (HAART) era (De Luca et al, 2006;Rhee et al, 2005). The mutations accumulate in two distinct but overlapping patterns (De Luca et al, 2006;Gonzales et al, 2003;Marcelin et al, 2004b;Yahi et al, 1999).…”

Section: Nrti Tams (Excision)mentioning

confidence: 99%

“…TAMs are also common in HIV-1 isolates from patients who began therapy in the pre-highly active antiretroviral therapy (HAART) era (De Luca et al, 2006;Rhee et al, 2005). The mutations accumulate in two distinct but overlapping patterns (De Luca et al, 2006;Gonzales et al, 2003;Marcelin et al, 2004b;Yahi et al, 1999). The type I pattern includes the M41L, L210W and T15Y mutations, respectively (De Luca et al, 2006;Miller et al, 2004).…”

Section: Nrti Tams (Excision)mentioning

confidence: 99%

“…The mutations accumulate in two distinct but overlapping patterns (De Luca et al, 2006;Gonzales et al, 2003;Marcelin et al, 2004b;Yahi et al, 1999). The type I pattern includes the M41L, L210W and T15Y mutations, respectively (De Luca et al, 2006;Miller et al, 2004). Type II patterns includes D67N, K70R, T215F and K219Q/E (Figure 2).…”

Section: Nrti Tams (Excision)mentioning

confidence: 99%

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Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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Polymorphism and drug selected mutations of reverse transcriptase gene in 102 HIV‐1 infected patients living in China

Liu

Henry³

et al. 2007

Journal of Medical Virology

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Few data are available for genotypic patterns within human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT) in drug-naive patients and RT inhibitor (RTI) treated patients in China. This study aimed at characterizing the polymorphism of RT HIV-1 in the absence of drug treatment and to identify known and unknown mutations emerging under RTI selective pressure. The HIV-1 RT gene from 21 drug-naive patients and 81 RTI treated patients from three provinces in China was analyzed. Most patients (>80%) received a triple regimen including stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP), or d4T plus lamivudine (3TC) and efavirenz (EFV), or zidovudine (AZT) +ddI + NVP. In untreated patients, four highly polymorphic positions were found (122, 200, 207, and 211). In treated patients, two patterns of resistance associated mutations (RAMs) were observed: (1) K65R (9.8%), L74V (7.4%), M184V (7.4%), Q151M (5%), and thymidine analogue mutations (TAMs) (9.3%) including T215Y (5.5%), in patients who underwent ddI + d4T + NVP. (2) T215Y (23%), M184V (20%), and TAMs (15.4%) in patients receiving d4T + 3TC + EFV. In all cases, a high prevalence of non-nucleoside RTIs (NNRTI) RAMs (41.9%) was found. Four RTI suspected new RAMs were described at position 142, 221, 224, and 228. An association between H221Y and L228H/R with Y181C was noted. These data highlight the predominant spread of NNRTI RAM in China, depict the specific genotypic pattern of RTI selected mutations in China, and suggest the association of newly described mutations with RTI therapy.

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Frequency and Treatment‐Related Predictors of Thymidine‐Analogue Mutation Patterns in HIV‐1 Isolates after Unsuccessful Antiretroviral Therapy

Cited by 24 publications

References 12 publications

Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Polymorphism and drug selected mutations of reverse transcriptase gene in 102 HIV‐1 infected patients living in China

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