Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy

Peuchant, Olivia; Thiébaut, Rodolphe; Capdepont, Sophie; Lavignolle-Aurillac, Valérie; Néau, Didier; Morlat, Philippe; Dabis, François; Fleury, Hervé; Masquelier, Bernard

doi:10.1097/qad.0b013e3283034953

Cited by 95 publications

(81 citation statements)

References 17 publications

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“…The effect of T215 revertants on the virologic response to a new ARV treatment regimen has been less marked than that of other drug resistance-associated mutations. Whereas transmitted NNRTI-associated mutations such as K103N have been shown to be strong predictors of virologic failure in persons receiving an NNRTI-containing regimen (1,12), transmitted T215 revertants have had a less pronounced effect (1,4,17,18,24,25). In our study, the overwhelming majority of persons with T215 revertants who received therapy experienced sustained virologic suppression.…”

Section: Vol 82 2008 Hiv-1 Variants In Persons With Rt Codon 215 Rementioning

confidence: 49%

Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations

Mitsuya

Varghese

Wang

et al. 2008

J Virol

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T215 revertant mutations such as T215C/D/E/S that evolve from the nucleoside reverse transcriptase (RT) inhibitor mutations T215Y/F have been found in about 3% of human immunodeficiency virus type 1 (HIV-1) isolates from newly diagnosed HIV-1-infected persons. We used a newly developed sequencing method-ultradeep pyrosequencing (UDPS; 454 Life Sciences)-to determine the frequency with which T215Y/F or other RT inhibitor resistance mutations could be detected as minority variants in samples from untreated persons that contain T215 revertants ("revertant" samples) compared with samples from untreated persons that lack such revertants ("control" samples). Among the 22 revertant and 29 control samples, UDPS detected a mean of 3.8 and 4.8 additional RT amino acid mutations, respectively. In 6 of 22 (27%) revertant samples and in 4 of 29 control samples (14%; P ‫؍‬ 0.4), UDPS detected one or more RT inhibitor resistance mutations. T215Y or T215F was not detected in any of the revertant or control samples; however, 4 of 22 revertant samples had one or more T215 revertants that were detected by UDPS but not by direct PCR sequencing. The failure to detect viruses with T215Y/F in the 22 revertant samples in this study may result from the overwhelming replacement of transmitted T215Y variants by the more fit T215 revertants or from the primary transmission of a T215 revertant in a subset of persons with T215 revertants.Human immunodeficiency virus type 1 (HIV-1) exists in vivo as a quasispecies consisting of innumerable genomic variants evolving through a process of mutation, recombination, and selection. The quasispecies nature of HIV-1 complicates the detection of drug-resistant HIV-1 variants because standard resistance testing using direct PCR dideoxynucleoside chain terminator sequencing rarely detects mutant variants present in fewer than 20% of circulating plasma viruses (14,20,26). We previously reported that ultradeep pyrosequencing (UDPS) using the 454 Life Sciences sequencing platform reliably detects minor variants that are missed by direct PCR chain terminator sequencing (26). In this study, we used UDPS to characterize the types of minor variants present in previously untreated HIV-1-infected persons who were found by direct PCR sequencing to have a class of mutations, T215 revertants, that occur almost exclusively among persons primarily infected with a virus previously exposed to selective antiretroviral (ARV) drug pressure. MATERIALS AND METHODS Persons and samples.We studied the treatment histories of all persons receiving medical care at the Kaiser Permanente Medical Care Program of Northern California (KPNC) between 1999 and 2007 who had genotypic resistance testing at Stanford University Hospital (SUH) and who were found to have an amino acid other than T, F, or Y at reverse transcriptase (RT) codon 215 ("215 revertant"). Available cryopreserved plasma samples from persons who were ARV naive, who had no evidence of a mixture that included Y or F, and who had plasma HIV-1 RNA levels Ն4.5 log copies/ml w...

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Section: Vol 82 2008 Hiv-1 Variants In Persons With Rt Codon 215 Rementioning

confidence: 49%

Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations

Mitsuya

Varghese

Wang

et al. 2008

J Virol

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“…Using ultrasensitive genotypic assays, many research groups have reported high proportions of transmitted DRM among ART-naïve individuals (15,30,32,37,48,58,65), but these findings are not consistent with the descriptions of mono-or oligoclonal transmission in the env coding region by SGS and UDS (1,19,25,33). The primary goal of this analysis was to investigate whether detected minority viral variants in the earliest part of HIV-1 infection were (i) truly transmitted, (ii) a consequence of viral evolution and selection early after transmission, (iii) technical errors in highly sensitive detection methods, or (iii) de novo mutations resulting as a consequence of the high error rate of HIV-1 replication.…”

Section: Discussionmentioning

confidence: 99%

“…It appears, however, to be increasing in these settings as well (2,14,51). Using more-sensitive genotypic assays, different research groups (15,30,32,37,48,58,65) have reported higher proportions of transmitted DRM in ART-naive individuals. The clinical importance of these low-level DRM remains unclear, as they have been associated with clinical consequences in some (21,24,32,36,37,40,46,54,55,63,66,71) but not all (30,47,58) studies.…”

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confidence: 99%

Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Gianella

Delport

Pacold

et al. 2011

J Virol

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Reports of a high frequency of the transmission of minority viral populations with drug-resistant mutations (DRM) are inconsistent with evidence that HIV-1 infections usually arise from mono-or oligoclonal transmission. We performed ultradeep sequencing (UDS) of partial HIV-1 gag, pol, and env genes from 32 recently infected individuals. We then evaluated overall and per-site diversity levels, selective pressure, sequence reproducibility, and presence of DRM and accessory mutations (AM). To differentiate biologically meaningful mutations from those caused by methodological errors, we obtained multinomial confidence intervals (CI) for the proportion of DRM at each site and fitted a binomial mixture model to determine background error rates for each sample. We then examined the association between detected minority DRM and the virologic failure of first-line antiretroviral therapy (ART). Similar to other studies, we observed increased detection of DRM at low frequencies (average, 0.56%; 95% CI, 0.43 to 0.69; expected UDS error, 0.21 ؎ 0.08% mutations/site). For 8 duplicate runs, there was variability in the proportions of minority DRM. There was no indication of increased diversity or selection at DRM sites compared to other sites and no association between minority DRM and AM. There was no correlation between detected minority DRM and clinical failure of first-line ART. It is unlikely that minority viral variants harboring DRM are transmitted and maintained in the recipient host. The majority of low-frequency DRM detected using UDS are likely errors inherent to UDS methodology or a consequence of error-prone HIV-1 replication.Using standard population-based genotypic assays of HIV from individuals not yet treated with antiretroviral drugs, several studies (43,64,69,76) have estimated the rate of transmitted drug resistance to be between 8 and 27% in countries with the highest rates of antiretroviral therapy (ART) use. In resource-limited settings, in which the introduction of ART has been more recent, the estimated frequency of transmitted drug resistance mutations (DRM) is substantially lower (41). It appears, however, to be increasing in these settings as well (2,14,51). Using more-sensitive genotypic assays, different research groups (15,30,32,37,48,58,65) have reported higher proportions of transmitted DRM in ART-naive individuals. The clinical importance of these low-level DRM remains unclear, as they have been associated with clinical consequences in some (21,24,32,36,37,40,46,54,55,63,66,71) but not all (30, 47, 58) studies.Highly sensitive assays for detecting low-frequency DRM include point mutation assays and high-resolution sequencing techniques. Point mutation assays, such as allele-specific PCR, can detect DRM at frequencies as low as 0.01% of the sampled viral population (31,45,53,54), but they do not provide information about the sequence context surrounding a given DRM and may be prone to false positives at the lower level of detection (22). High-resolution sequencing techniques, such as single ge...

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“…Plasma viral samples obtained during PHI that lacked either the M184V or the K103N mutation were evaluated by AS-PCR to detect viral populations that possibly carried these mutations (sensitivity, Ϸ1%); sensitivity and specificity were monitored using positive and negative controls. Purified PCR products of the genotyped samples were used as described previously (7,10) in an assay in which the 5Ј ends of forward primers were subjected to an inosine modification. The primers used were IN_K103N (5Ј-CCGCAGGGTTAAAAAAGAI C-3Ј; nucleotides [nt] 2839 to 2858) and Pol 3002 (5Ј-CTGTG GAAGCACATTGTACTG-3Ј; nt 2982 to 3002) for detection of K103N and IN_M184V (5Ј-CCAGACATAGTTATCTATC AATAIG-3Ј; nt 3075 to 3099) and N35 (5Ј-CCTACTAACTT CTGTATGTCATTGACAGTCCAGCT-3Ј; nt 3300 to 3333) for detection of M184V.…”

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confidence: 99%

“…In the absence of drug pressure, viruses harboring M184V can rapidly revert to the wild type or deselect this mutation and, consequently, are less well detected by bulk sequencing (12). One recent report found an association between the presence of baseline minority resistance variants and nonresponsiveness to highly active antiretroviral therapy (5), although other studies have not obtained similar results (8,10). Although M184V-containing viruses can rapidly revert to the wild type, the persistence of M184V-containing strains is of concern in the management of antiretroviral therapy.…”

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confidence: 99%

Detection of Human Immunodeficiency Virus (HIV) Type 1 M184V and K103N Minority Variants in Patients with Primary HIV Infection

Toni

Asahchop

Moïsi

et al. 2009

Antimicrob Agents Chemother

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We used an allele-specific real-time PCR assay to explore the presence of K103N and M184V minority species among primary human immunodeficiency virus (HIV) infections and their potential influence in HIV transmission. Thirty randomly chosen antiretroviral drug-naive patients lacking both the K103N and the M184V mutations as determined by conventional sequencing methods were studied, and K103N and M184V viral minority species were found in three (10%) and four (11%) patients, respectively.

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Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy

Abstract: The transmission of majority-resistant variants, but not minority-resistant variants, influenced the response to antiretroviral therapy in this prospective study. The detection of the transmission of minority-resistant variants warrants further clinical validation.

Cited by 95 publications

References 17 publications

Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations

Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations

Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Detection of Human Immunodeficiency Virus (HIV) Type 1 M184V and K103N Minority Variants in Patients with Primary HIV Infection

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