Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing

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MARC

Hedskog, CharlotteKarolinska Institutet (author)

Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing

Article/chapterEnglish2010

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2010-07-07
Public Library of Science (PLoS),2010
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LIBRIS-ID:oai:DiVA.org:kth-29504
https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-29504URI
https://doi.org/10.1371/journal.pone.0011345DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:120973512URI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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QC 20110203
Background: Ultra-deep pyrosequencing (UDPS) allows identification of rare HIV-1 variants and minority drug resistance mutations, which are not detectable by standard sequencing. Principal Findings: Here, UDPS was used to analyze the dynamics of HIV-1 genetic variation in reverse transcriptase (RT) (amino acids 180-220) in six individuals consecutively sampled before, during and after failing 3TC and AZT containing antiretroviral treatment. Optimized UDPS protocols and bioinformatic software were developed to generate, clean and analyze the data. The data cleaning strategy reduced the error rate of UDPS to an average of 0.05%, which is lower than previously reported. Consequently, the cut-off for detection of resistance mutations was very low. A median of 16,016 (range 2,406-35,401) sequence reads were obtained per sample, which allowed detection and quantification of minority resistance mutations at amino acid position 181, 184, 188, 190, 210, 215 and 219 in RT. In four of five pre-treatment samples low levels (0.07-0.09%) of the M184I mutation were observed. Other resistance mutations, except T215A and T215I were below the detection limit. During treatment failure, M184V replaced M184I and dominated the population in combination with T215Y, while wild-type variants were rarely detected. Resistant virus disappeared rapidly after treatment interruption and was undetectable as early as after 3 months. In most patients, drug resistant variants were replaced by wild-type variants identical to those present before treatment, suggesting rebound from latent reservoirs. Conclusions: With this highly sensitive UDPS protocol preexisting drug resistance was infrequently observed; only M184I, T215A and T215I were detected at very low levels. Similarly, drug resistant variants in plasma quickly decreased to undetectable levels after treatment interruption. The study gives important insights into the dynamics of the HIV-1 quasispecies and is of relevance for future research and clinical use of the UDPS technology.

Subject headings and genre

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
HUMAN-IMMUNODEFICIENCY-VIRUS
CD4(+) T-CELLS
TYPE-1 REVERSE-TRANSCRIPTASE
DRUG-RESISTANCE MUTATIONS
IN-VIVO
ANTIRETROVIRAL THERAPY
VIRAL VARIANTS
INFECTION
NAIVE
REPLICATION
Cell and molecular biology
Cell- och molekylärbiologi

Added entries (persons, corporate bodies, meetings, titles ...)

Mild, MattiasKarolinska Institutet (author)
Jernberg, JohannaKarolinska Institutet (author)
Sherwood, EllenKarolinska Institutet (author)
Bratt, GöranKarolinska Institutet (author)
Leitner, Thomas (author)
Lundeberg, JoakimKTH,Genteknologi(Swepub:kth)u1qkn9kw (author)
Andersson, BjörnKarolinska Institutet (author)
Albert, Jan (author)
Karolinska InstitutetGenteknologi (creator_code:org_t)

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In:PLOS ONE: Public Library of Science (PLoS)5:7, s. e11345-1932-6203

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