Linked dual-class HIV resistance mutations are associated with treatment failure

Boltz, Valerie F.; Shao, Wei; Bale, Michael J.; Halvas, Elias K.; Luke, Brian T.; McIntyre, James; Schooley, Robert T.; Lockman, Shahin; Currier, Judith S.; Sawe, Fred; Hogg, Evelyn; Hughes, Michael D.; Kearney, Mary F.; Coffin, John M.; Mellors, John W.

doi:10.1172/jci.insight.130118

Cited by 11 publications

(9 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although other programs that calculate mutation frequencies from such data are available (Houssaini et al, 2013; SahBandar et al, 2017), they only calculate the frequencies of individual resistance mutations in the HIV-1 population and do not report their linkage. Mutations linked on the same HIV-1 genomes have been shown to be associated with virologic failure even when present at the same or lower levels as single mutations (Boltz et al, 2019) and, therefore, are important to detect and report for investigational use. Of importance, HIV-DRLink was developed for the detection of linked mutations from NGS data generated by methods such as uSGS (Boltz et al, 2016) and other similar methods (Jabara et al, 2011; Zhou et al, 2015) where PCR recombination has been either eliminated, as is the case with uSGS, or shown to be minimal.…”

Section: Discussionmentioning

confidence: 99%

“…The Stanford HIV Database (Stanford HIVdb) is a reliable and accurate tool for interpreting HIV drug resistance in population genotypes (Tang, Liu, and Shafer, 2012) (https://hivdb.stanford.edu/). While important, the detection of pre-existing single drug resistance mutations misses the significance of resistance mutations that are linked on the same viral genomes and that were recently shown to be associated with cART failure (Boltz et al, 2019). In fact, detection of pre-existing, linked, dual-class resistance mutations is a better predictor of cART failure than detection of pre-existing, single resistance mutations (Boltz et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…While important, the detection of pre-existing single drug resistance mutations misses the significance of resistance mutations that are linked on the same viral genomes and that were recently shown to be associated with cART failure (Boltz et al, 2019). In fact, detection of pre-existing, linked, dual-class resistance mutations is a better predictor of cART failure than detection of pre-existing, single resistance mutations (Boltz et al, 2019). One difficulty in the interpretation of linked mutations is that bulk PCR may result in artifactual recombination (Shao et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data

Shao

Hattori

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The prevalence of HIV-1 drug resistance is increasing worldwide and monitoring its emergence is important for the successful management of populations receiving combination antiretroviral therapy (cART). Using Ultrasensitive Single-Genome Sequencing (uSGS), a next-generation method that avoids PCR bias and PCR recombination, a recent report showed that pre-existing dual-class drug resistance mutations linked on the same viral genomes were predictive of treatment failure while unlinked mutations were not. Because of the large numbers of sequences generated by uSGS and other next-generation sequencing methods, it is difficult to assess each sequence individually for linked resistance mutations. Several software/programs exist to report the frequencies of individual mutations in large datasets but they provide no information on their linkage. Here, we report the HIV-DRLink program, a research tool that provides mutation frequencies in the total dataset as well as their linkage to other mutations conferring resistance to the same or different drug classes. The HIV-DRLink program should only be used on datasets generated by methods that eliminate artifacts due to PCR recombination, for example, standard Single-Genome Sequencing (SGS) or Ultrasensitive Single-Genome Sequencing (uSGS). HIV-DRLink is exclusively a research tool and is not intended to inform clinical decisions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data

Shao

Hattori

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Multiplex amplified samples with unique index sequences greatly reduced the complexity of SGS allowing multiple amplified cDNA products in the same sequencing run. Subsequently the incorporation of cDNA barcoding into NGS increased the sensitivity for minor variant detection [ 62 , 63 ] even more than SGS [i.e., ultrasensitive SGS (uSGS) [ 64 ]] and was recently used to uncover rare mutations linked on the same HIV-1 genome [ 65 ].…”

Section: Hiv-1 Sequencing Technologies For Sars-cov-2mentioning

confidence: 99%

Adaptation of advanced clinical virology assays from HIV-1 to SARS-CoV-2

McCormick

Mellors

Jacobs

2020

Current Opinion in HIV and AIDS

Self Cite

View full text Add to dashboard Cite

Purpose of review In response to the HIV–AIDS pandemic, great strides have been made in developing molecular methods that accurately quantify nucleic acid products of HIV-1 at different stages of viral replication and to assess HIV-1 sequence diversity and its effect on susceptibility to small molecule inhibitors and neutralizing antibodies. Here, we review how knowledge gained from these approaches, including viral RNA quantification and sequence analyses, have been rapidly applied to study SARS-CoV-2 and the COVID-19 pandemic. Recent findings Recent studies have shown detection of SARS-CoV-2 RNA in blood of infected individuals by reverse transcriptase PCR (RT-PCR); and, as in HIV-1 infection, there is growing evidence that the level of viral RNA in plasma may be related to COVID disease severity. Unlike HIV-1, SARS-CoV-2 sequences are highly conserved limiting SARS-CoV-2 sequencing applications to investigating interpatient genetic diversity for phylogenetic analysis. Sensitive sequencing technologies, originally developed for HIV-1, will be needed to investigate intrapatient SARS-CoV-2 genetic variation in response to antiviral therapeutics and vaccines. Summary Methods used for HIV-1 have been rapidly applied to SARS-CoV-2/COVID-19 to understand pathogenesis and prognosis. Further application of such methods should improve precision of therapy and outcome.

show abstract

“…Although important, the detection of pre-existing single drug resistance mutations misses the significance of resistance mutations that are linked on the same viral genomes and were recently shown, in one study, to be associated with cART failure. 8 One difficulty in the interpretation of linked mutations is that bulk polymerase chain reaction (PCR) may result in artifactual recombination. 9 Therefore, identifying linked mutations can only be applied to sequences obtained using methods that eliminate PCR recombination in conjunction with pipelines that omit sequences resulting from PCR recombination and possible nucleotide mixtures, such as single-genome sequencing (SGS), 10 ultrasensitive single-genome sequencing (uSGS), 11 or other similar next-generation sequencing (NGS) methods.…”

Section: Introductionmentioning

confidence: 99%

Short Communication: HIV-DRLink: A Tool for Reporting Linked HIV-1 Drug Resistance Mutations in Large Single-Genome Data Sets Using the Stanford HIV Database

Shao

Boltz

Hattori

et al. 2020

AIDS Research and Human Retroviruses

Self Cite

View full text Add to dashboard Cite

The prevalence of HIV-1 drug resistance is increasing worldwide and monitoring its emergence is important for the successful management of populations receiving combination antiretroviral therapy. It is likely that pre-existing drug resistance mutations linked on the same viral genomes are predictive of treatment failure. Because of the large number of sequences generated by ultrasensitive single-genome sequencing (uSGS) and other similar next-generation sequencing methods, it is difficult to assess each sequence individually for linked drug resistance mutations. Several software/programs exist to report the frequencies of individual mutations in large data sets, but they provide no information on linkage of resistance mutations. In this study, we report the HIV-DRLink program, a research tool that provides resistance mutation frequencies as well as their genetic linkage by parsing and summarizing the Sierra output from the Stanford HIV Database. The HIV-DRLink program should only be used on data sets generated by methods that eliminate artifacts due to polymerase chain reaction recombination, for example, standard single-genome sequencing or uSGS. HIV-DRLink is exclusively a research tool and is not intended to inform clinical decisions.

show abstract

Linked dual-class HIV resistance mutations are associated with treatment failure

Cited by 11 publications

References 42 publications

HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data

HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data

Adaptation of advanced clinical virology assays from HIV-1 to SARS-CoV-2

Short Communication: HIV-DRLink: A Tool for Reporting Linked HIV-1 Drug Resistance Mutations in Large Single-Genome Data Sets Using the Stanford HIV Database

Contact Info

Product

Resources

About