Future technologies for monitoring HIV drug resistance and cure

Parikh, Urvi M.; McCormick, Kevin D.; Zyl, Gert van; Mellors, John W.

doi:10.1097/coh.0000000000000344

Cited by 46 publications

(40 citation statements)

References 53 publications

(38 reference statements)

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“…Third, resistance mutations may exist in the intra-host virus population at frequency below the detection threshold. Mutations are typically detected by Sanger sequencing-based methods, while next-generation sequencing methods could improve upon the sensitivity of detecting mutations [57].…”

Section: Discussionmentioning

confidence: 99%

Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

Posada-Céspedes

Zyl

Montazeri

et al. 2020

Preprint

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Although combination antiretoviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Here, we present a methodology for the comparison of mutational pathways in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational pathways from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models on a large number of resistance mutations and develop a statistical test to assess differences in the inferred mutational pathways between two groups. We apply this method to the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional data set of South African individuals living with HIV-1 subtype C, as well as a genotype data set of subtype B infections derived from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. Our results also show that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Furthermore, the maximum likelihood mutational networks for subtypes B and C share only 7 edges (Jaccard distance 0.802) and imply many different evolutionary pathways. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational pathways between any two groups.Author summaryThere is a disparity in the distribution of infections by HIV-1 subtype in the world. Subtype B is predominant in America, Western Europe and Australia, and most therapeutic strategies are based on research and clinical studies on this subtype. However, non-B subtypes represent the majority of global HIV-1 infections; e.g., subtype C alone accounts for nearly half of all HIV-1 infections. We present a statistical framework enabling the comparison of patterns of accumulating mutations in different HIV-1 subtypes. Specifically, we study lopinavir resistance pathways in HIV-1 subtypes B versus C, but the methodology can be generally applied to compare the temporal ordering of genetic events in different subgroups.

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Section: Discussionmentioning

confidence: 99%

Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

Posada-Céspedes

Zyl

Montazeri

et al. 2020

Preprint

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“…Co-infection with HIV/HCV develop a higher rate of liver fibrosis, cirrhosis, hepatocellular carcinoma and death (16)(17)(18). Due to, high genetic diversity of HIV, no vaccine and decisive treatment are available against HIV infection (19,20).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of hepatitis C virus among HIV-infected patients

Zayedi¹,

Makvandi²,

Teimoori³

et al. 2020

IJM

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Background and Objectives: Hepatitis C virus and Human Immunodeficiency Virus (HIV) share the same rate of transmis- sion. HIV/HCV co-infected individuals may result in faster progression of liver fibrosis and highly increase the risk of cir- rhosis, hepatocellular carcinoma development. Thus this study was conducted to determine co-infection of HCV genotypes in positive HIV patients in Ahvaz city, Iran. Materials and Methods: The sera samples were collected from confirmed 78 infected HIV, 67 (85.89%) males and 11 (14.1%) females. All sera samples were tested for HCV Ab using ELISA test. The HCV Ab positive samples were tested for detection of 5' untranslated (UTR) and core regions of HCV genome using nested RT-PCR. The PCR products of 5UTR and core regions were sequenced to determine HCV genotypes. Results: Among the 78 infected HIV, 25 (32.05%) cases including 20 (25.64%) males and 5 (6.41%) females were positive for HCV Ab (p=0.316). 53 (67.94%) of HIV patients were negative for HCV Ab. Among 25 positive HCV Ab, 19 (24.35%) cases including 15 (19.23%) males and 4 (5.12%) females were positive for HCV RNA (p=0.447). The PCR products of 5 positive samples were randomly sequenced. The results of sequences and alignments showed that the detected HCV geno- types were three 3a and two 1a. The occurrence of genotype HCV 1a was found in one male injecting drug user Injecting Drug User (IDU) and one female. The HCV 3a genotype was detected in the three males IDU. Conclusion: The results of this survey indicated that 32.05% of HIV patients were positive for HCV Ab, among them 24.35% were positive HCV RNA. HCV genotype 3a was dominant and detected in the three males IDU. Regarding the consequences of HIV/HCV co-infection, it is suggested that HCV RNA detection should be regularly checked in individuals infected with HIV.

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“…drug resistant, high transmission) could be propagated [1,3]. Therefore, sequencing and analysis of the HIV quasispecies is important for improving personalized treatment plan, developing early prevention action, designing more effective vaccine for patients [1,3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Even though the next generation sequencing (NGS) technology of Illumina shortgun sequencing offers improved variant detection ability (~1% detection limit) over the traditional Sanger-based sequencing method (~20% detection limit) [4,5], both have the common weakness on sequencing HIV strains, that is, their detection of the mutations is at the individual mutation level and the important linkage relationship among mutations is lost during the procedure [6]. Furthermore, the recently emerging third generation sequencing, PacBio, can continuously sequence up to 10 kb for each read which in theory not only provides high detection sensitivity but also maintain the relationship of mutations [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…However, the high-noise nature of PacBio reads and lacks of effective data analysis tools still pose a barrier to fully utilize its power in the field of HIV genetics [6,8]. Several works have addressed the challenges with different data analysis strategies, such as tag focusing, error-correction, and clustering [4,5]. Some shortages of these works include but are not limited to: 1.…”

Section: Introductionmentioning

confidence: 99%

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Towards Personalized Medicine: An Improved De Novo Assembly Procedure for Early Detection of Drug Resistant HIV Minor Quasispecies in Patient Samples

Huang¹,

Sam²,

Du³

et al. 2018

Bioinformation

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The third-generation sequencing technology, PacBio, has shown an ability to sequence the HIV virus amplicons in their full length. The long read of PaBio offers a distinct advantage to comprehensively understand the virus evolution complexity at quasispecies level (i.e. maintaining linkage information of variants) comparing to the short reads from Illumina shotgun sequencing. However, due to the highnoise nature of the PacBio reads, it is still a challenge to build accurate contigs at high sensitivity. Most of previously developed NGS assembly tools work with the assumption that the input reads are fairly accurate, which is largely true for the data derived from Sanger or Illumina technologies. When applying these tools on PacBio high-noise reads, they are largely driven by noise rather than true signal eventually leading to poor results in most cases. In this study, we propose the de novo assembly procedure, which comprises a positivefocused strategy, and linkage-frequency noise reduction so that it is more suitable for PacBio high-noise reads. We further tested the unique de novo assembly procedure on HIV PacBio benchmark data and clinical samples, which accurately assembled dominant and minor populations of HIV quasispecies as expected. The improved de novo assembly procedure shows potential ability to promote PacBio technology in the field of HIV drug-resistance clinical detection, as well as in broad HIV phylogenetic studies.

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Future technologies for monitoring HIV drug resistance and cure

Cited by 46 publications

References 53 publications

Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

Prevalence of hepatitis C virus among HIV-infected patients

Towards Personalized Medicine: An Improved De Novo Assembly Procedure for Early Detection of Drug Resistant HIV Minor Quasispecies in Patient Samples

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