HIV Infection and Antiretroviral Therapy: Effect on Hepatitis C Virus Quasispecies Variability

Shuhart, Margaret C.; Sullivan, Daniel G.; Bekele, Kirubeal; Harrington, Robert D.; Kitahata, Mari M.; Mathisen, T. L.; Thomassen, Lisa V.; Emerson, Scott S.; Gretch, David R.

doi:10.1086/502974

Cited by 34 publications

(44 citation statements)

References 44 publications

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“…HIV-HCV coinfection was associated with reduced HVR1 diversity compared to monoinfection, and our data help us to understand why this point has been controversial in previous literature (4,27,31,34,36,39,43). There was considerable variation in HCV diversity among subjects within each group, which is particularly evident thanks to the depth of the pyrosequencing data, suggesting that factors in addition to HIV coinfection also affect diversity.…”

Section: Discussionsupporting

confidence: 51%

Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing

Wang

Sherrill-Mix

Chang

et al. 2010

J Virol

136

135

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Hepatitis C virus (HCV) replication in infected patients produces large and diverse viral populations, which give rise to drug-resistant and immune escape variants. Here, we analyzed HCV populations during transmission and diversification in longitudinal and cross-sectional samples using 454/Roche pyrosequencing, in total analyzing 174,185 sequence reads. To sample diversity, four locations in the HCV genome were analyzed, ranging from high diversity (the envelope hypervariable region 1 [HVR1]) to almost no diversity (the 5 untranslated region [UTR]). For three longitudinal samples for which early time points were available, we found that only 1 to 4 viral variants were present, suggesting that productive infection was initiated by a very small number of HCV particles. Sequence diversity accumulated subsequently, with the 5 UTR showing almost no diversification while the envelope HVR1 showed >100 variants in some subjects. Calculation of the transmission probability for only a single variant, taking into account the measured population structure within patients, confirmed initial infection by one or a few viral particles. These findings provide the most detailed sequence-based analysis of HCV transmission bottlenecks to date. The analytical methods described here are broadly applicable to studies of viral diversity using deep sequencing.Hepatitis C virus (HCV) is a positive-strand enveloped RNA virus of the flavivirus family. HCV infects ϳ170 million people worldwide with a high rate of persistence (1, 2) and is a major etiological agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The current standard of therapy is the combined use of pegylated alpha interferon (IFN-␣) and ribavirin (9), although there are substantial limitations due to toxicity and resistance profiles (47). Recent development of various small-molecule inhibitors that specifically target HCV offer some promise (13), but challenges still remain because the size and diversity of viral populations promote rapid development of drug resistance (28,42). In an infected individual, serum HCV RNA levels can reach 10 to 100 million IU/ml (40). The viral RNA polymerase is estimated to make 1 error per 10,000 to 100,000 bp copied (22), but the viral genome is only 9,600 bases, resulting in diversification of the viral population, so that most viral genomes differ in sequence from the population consensus (16,20,21). Thus, when antiviral pressure is exerted on a viral population, sequence variants with reduced sensitivity may expand in the presence of the selective pressure (30, 41) and cause resistance (37). Consistent with this, differential sequence diversity in HCV populations has been linked to clinical outcome (7,8).The size and complexity of HCV populations has made their analysis challenging. However, new deep-sequencing and bioinformatics methods are well suited to analyzing this problem. Using the 454/Roche technology, it is possible to generate more than 10 8 bases of DNA sequence in a single 1-day run, albeit in fragments...

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Section: Discussionsupporting

confidence: 51%

Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing

Wang

Sherrill-Mix

Chang

et al. 2010

J Virol

136

135

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“…45 However, a recent report using clonal frequency analysis through heteroduplex mobility assay did not find any independent association between CD4 count and quasispecies complexity or diversity when analyzing 28 HCV/HIV coinfected patients. 46 In our current study neither quasispecies complexity nor dynamics correlated with CD4ϩ cell count. However, very high HIV RNA plasma levels of Ͼ100,000 copies/mL were associated with lack of escape mutations, as suggested by the stability of bands over the time.…”

Section: Discussioncontrasting

confidence: 61%

“…However, the median duration of HAART in that study was 46 months. 46 An intriguing finding in our study was a relationship between changes in SSCP band positions, indicating quasispecies sequence changes, and recent IDU. This is compatible with superinfection with a new virus.…”

Section: Discussionmentioning

confidence: 58%

Hepatitis C virus quasispecies in HIV-infected women: Role of injecting drug use and highly active antiretroviral therapy (HAART)

et al. 2007

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“…Further investigation could evaluate the functional effects of variation in these amino acid positions. Elevated non-synonymous to synonymous substitution rate ratios can indicate positive selection (Li and Graur, 2000), and have been reported for HCV-HIVcoinfected patients undergoing HAART (Babik and Holodniy, 2003;Shuhart et al, 2006).…”

Section: Analysis Of Resistance Mutationsmentioning

confidence: 99%

Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research

Hraber

Leach

Reilly

et al. 2007

Antivir Chem Chemother

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The hepatitis C virus (HCV) resource at Los Alamos (hcv.lanl.gov) provides access to multiple databases: one containing annotated sequences and the other a repository of immunogenic epitopes. They are derived from databases originally developed for HIV research (hiv.lanl.gov). HCV and HIV are RNA viruses with relatively compact genomes (around 10 kb) that are extraordinarily variable, both within and between hosts. This diversity requires methods to track and exclude variants from an individual infection or from epidemiologically related infections, and tools to analyse the variation. The HCV immunology database contains a curated inventory of immunogenic epitopes and information about their interaction with the host immune system, with associated retrieval and analysis tools. This interactive resource provides flexible retrieval tools for sequences, epitopes, clinical information, and metadata, as well as utilities for scientific data analysis, to investigators with internet access and a web browser. This paper describes the types of data and the services that these databases offer, the tools they provide, and their configuration and use. Examples of applications to clonal analysis for drugresistance mutations are shown.

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HIV Infection and Antiretroviral Therapy: Effect on Hepatitis C Virus Quasispecies Variability

Cited by 34 publications

References 44 publications

Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing

Hepatitis C Virus Transmission Bottlenecks Analyzed by Deep Sequencing

Hepatitis C virus quasispecies in HIV-infected women: Role of injecting drug use and highly active antiretroviral therapy (HAART)

Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research

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