High Sequence Conservation of Human Immunodeficiency Virus Type 1 Reverse Transcriptase under Drug Pressure despite the Continuous Appearance of Mutations

Ceccherini‐Silberstein, Francesca; Gago, Federico; Santoro, Maria Mercedes; Gori, Caterina; Svicher, Valentina; Rodrı́guez-Barrios, Fátima; D’Arrigo, Roberta; Ciccozzi, Massimo; Bertoli, Ada; Monforte, Antonella d’Arminio; Balzarini, Jan; Antinori, Andrea; Perno, Carlo Federico

doi:10.1128/jvi.79.16.10718-10729.2005

Cited by 53 publications

(66 citation statements)

References 66 publications

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“…Approximately 88% (n=1,254) of tests used in this analysis were performed by means of a commercially available kit (ViroSeq HIV-1 Genotyping System; Abbott Molecular, Des Plains, IL, USA) according to the manufacturer's recommendations, as described above [24]. The remaining 176 tests were performed by means of the Trugene-HIV-1 Genotyping-Kit (TG HIV-1; Bayer HealthCare LLC, Tarrytown, NY, USA) [25].…”

Section: Genotypingmentioning

confidence: 99%

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

et al. 2013

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Background: We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern firstline therapies. Methods: A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006-2009) were grouped according to levels of pre-HAART viraemia (≤30,000, 30,001-100,000, 100,001-300,000, 300,001-500,000 and >500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia ≤50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values >50 copies/ml after virological success) were evaluated by Kaplan-Meier curves and Cox regression analyses. Results: Median pre-HAART viraemia was 5.1 log 10 copies/ml (IQR 4.5-5.5), and 53% of patients had viraemia >100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was >90% in all pre-HAART viraemia ranges, with the only exception of range >500,000 copies/ml (virological success =83%; P<0.001). Higher pre-HAART viraemia was tightly correlated with longer median time to achieve virological success. Cox multivariable estimates confirmed this result: patients with pre-HAART viraemia >500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4 + T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P<0.001). Pre-HAART viraemia >500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 (P=0.050). Conclusions: At the time of modern HAART, and even though an average >90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with >500,000 copies/ml represent a significant population that may deserve special attention.HAART has significantly extended the time to development of AIDS and to death in HIV-infected individuals [1,2]. Its efficacy in suppression of plasma HIV-1 RNA to undetectable levels, and in increasing CD4 + T-cell count, is well documented in several clinical trials [3][4][5][6].Despite years of great progress in treating AIDS, however, in some patients starting their first treatment; the effectiveness of HAART is still not sufficient, with consequent virological failures [7][8][9]. These failures can be caused by several factors, such as drug potency, drug

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Section: Genotypingmentioning

confidence: 99%

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

et al. 2013

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“…For instance, recent studies have identified novel mutations positively associated with NNRTI treatment (9,10,18,34,36); however, the exact role of these mutations in contributing to NNRTI resistance remains unclear. Moreover, other studies have shown also the involvement in NNRTI resistance of mutations conferring resistance to NRTI, thus suggesting an interplay between NRTI-and NNRTI-characteristic mutations (12,27,40,41,45,46).…”

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Characterization and Structural Analysis of Novel Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involved in the Regulation of Resistance to Nonnucleoside Inhibitors

Ceccherini‐Silberstein

Svicher

Sing

et al. 2007

J Virol

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Resistance to antivirals is a complex and dynamic phenomenon that involves more mutations than are currently known. Here, we characterize 10 additional mutations (L74V, K101Q, I135M/T, V179I, H221Y, K223E/Q, and L228H/R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase which are involved in the regulation of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). These mutations are strongly associated with NNRTI failure and strongly correlate with the classical NNRTI resistance mutations in a data set of 1,904 HIV-1 B-subtype pol sequences from 758 drug-naïve patients, 592 nucleoside reverse transcriptase inhibitor (NRTI)-treated but NNRTI-naïve patients, and 554 patients treated with both NRTIs and NNRTIs. In particular, L74V and H221Y, positively correlated with Y181C, were associated with an increase in Y181C-mediated resistance to nevirapine, while I135M/T mutations, positively correlated with K103N, were associated with an increase in K103N-mediated resistance to efavirenz. In addition, the presence of the I135T polymorphism in NNRTI-naïve patients significantly correlated with the appearance of K103N in cases of NNRTI failure, suggesting that I135T may represent a crucial determinant of NNRTI resistance evolution. Molecular dynamics simulations show that I135T can contribute to the stabilization of the K103N-induced closure of the NNRTI binding pocket by reducing the distance and increasing the number of hydrogen bonds between 103N and 188Y. H221Y also showed negative correlations with type 2 thymidine analogue mutations (TAM2s); its copresence with the TAM2s was associated with a higher level of zidovudine susceptibility. Our study reinforces the complexity of NNRTI resistance and the significant interplay between NRTI-and NNRTI-selected mutations. Mutations beyond those currently known to confer resistance should be considered for a better prediction of clinical response to reverse transcriptase inhibitors and for the development of more efficient new-generation NNRTIs.

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“…9,[42][43][44][45][46][47] Baseline polymorphisms in treatment-naive subjects within RT have been linked to resistance to RT inhibitors. 30,[48][49][50] It appears that CD8 þ T cell escape variants could become fixed and propagated through populations 47 in the same way viruses resistant to ART are transmitted. 51 An earlier study 52 proposed two rationales for the lack of reversion of CD8 þ T cell escape variants: the absence of a significant influence on viral fitness and the existence of CD8 þ T cell-mediated selective pressure restricted by a human leukocyte antigen (HLA) allele.…”

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“…27,41 However, synonymous nucleotide changes were usually observed to predominate among the surviving variant sequences and dN/dS tends to be <1 when there is a requirement to maintain protein function. [30][31][32] No drug resistance mutations were observed in the RT sequences amplified from the transmission pairs. Positive selection of codons 135, 162, 166, 207, and 211 occurred in >50% of the donor and the recipient RT sequences (Fig.…”

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Short Communication: Nucleotide Variation and Positively Selected Sites in HIV Type 1 Reverse Transcriptase Among Heterosexual Transmission Pairs

Shanmugasundaram

Solomon

Murugavel

et al. 2010

AIDS Research and Human Retroviruses

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Mutations in the env gene of HIV-1 have been the primary focus in most epidemiologically related cohort studies of virus evolution and very limited studies have focused on the reverse transcriptase (RT) region, the primary target of antiretroviral therapy (ART). Hence, we measured the selection pressure and searched for the positively selected sites in the RT sequences amplified from HIV-1-infected heterosexual transmission pairs. Married couples (n ¼ 10) who were ART naive were included in this study. Phylogenetic analysis, the measurement of synonymous and nonsynonymous ratio (dN/dS) and the interpatient nucleotide variation, was done. Phylogenetic analysis demonstrated distinct subclusters of the RT sequences from heterosexual transmission pairs and the median (IQR) nucleotide variation between the epidemiologically related transmission pairs was significantly ( p < 0.001) lower [0.01% (0.01-0.02%)] compared to the epidemiologically unrelated transmission pairs [0.04% (0.03-0.04%)]. The ratio of dN/dS was <1 and codons 135, 162, 166, 207, and 211 were positively selected in >50% of the donor and recipient RT sequences. Purifying selection pressure and low nucleotide variation in the RT sequences between epidemiologically related transmission pairs highlight its essential role in HIV-1 replication. The effect of the RT positively selected mutations that persist over time following transmission between individuals needs to be studied to determine the fitness cost of the mutations in vivo, which may possibly represent good targets for inclusion in HIV-1 vaccines.

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High Sequence Conservation of Human Immunodeficiency Virus Type 1 Reverse Transcriptase under Drug Pressure despite the Continuous Appearance of Mutations

Cited by 53 publications

References 66 publications

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

Characterization and Structural Analysis of Novel Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involved in the Regulation of Resistance to Nonnucleoside Inhibitors

Short Communication: Nucleotide Variation and Positively Selected Sites in HIV Type 1 Reverse Transcriptase Among Heterosexual Transmission Pairs

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