Trace amounts of sporadically reappearing HCV RNA can cause infection
Naga Suresh Veerapu, … , Todd M. Allen, Barbara Rehermann
Naga Suresh Veerapu, … , Todd M. Allen, Barbara Rehermann
Published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3469-3478. https://doi.org/10.1172/JCI73104.
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Research Article Virology

Trace amounts of sporadically reappearing HCV RNA can cause infection

Abstract

Successful hepatitis C virus (HCV) treatment is defined as the absence of viremia 6 months after therapy cessation. We previously reported that trace amounts of HCV RNA, below the sensitivity of the standard clinical assay, can reappear sporadically in treatment responders. Here, we assessed the infectivity of this RNA and infused 3 chimpanzees sequentially at 9-week intervals with plasma or PBMCs from patients who tested positive for trace amounts of HCV RNA more than 6 months after completing pegylated IFN-α/ribavirin therapy. A fourth chimpanzee received HCV RNA–negative plasma and PBMCs from healthy blood donors. The 3 experimental chimpanzees, but not the control chimpanzee, generated HCV-specific T cell responses against nonstructural and structural HCV sequences 6–10 weeks after the first infusion of patient plasma and during subsequent infusions. In 1 chimpanzee, T cell responses declined, and this animal developed high-level viremia at week 27. Deep sequencing of HCV demonstrated transmission of a minor HCV variant from the first infusion donor that persisted in the chimpanzee for more than 6 months despite undetectable systemic viremia. Collectively, these results demonstrate that trace amounts of HCV RNA, which appear sporadically in successfully treated patients, can be infectious; furthermore, transmission can be masked in the recipient by an extended eclipse phase prior to establishing high-level viremia.

Authors

Naga Suresh Veerapu, Su-Hyung Park, Damien C. Tully, Todd M. Allen, Barbara Rehermann

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Figure 4

Transmission of a minor quasispecies with a unique HVR1 sequence.

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Transmission of a minor quasispecies with a unique HVR1 sequence. (A) Co...
(A) Comparison of HCV amino acid sequence diversity in the source patient (at the last time point during PegIFN/RBV therapy at which the patient still had sufficient viremia to sequence [11,360 copies/ml], i.e., less than 6 weeks prior to the first negative quantitative assay) and in infected chimpanzee A3A013 (week 27). Plotted is the percentage of amino acid diversity at each position spanning E2 to NS5B with respect to the dominant amino acid found within each sample. (B) Comparison of the dominant HCV E2-to-NS5B nucleotide sequence in chimpanzee A3A013 using the same biospecimens as in A. Percentages indicate the prevalence of the respective quasispecies among the detected sequences. The scale bar corresponds to 0.005 substitutions per site. (C) Comparison of the HCV HVR1 sequences in chimpanzee A3A013 and in the source patient using the same biospecimens as in A. Sequences are shown relative to the dominant HVR variant in the source patient (top panel) or chimpanzee (bottom panel), with dots indicating conserved residues. The frequency of each HVR1 variant among the total number of HVR1 variants in the patient or chimpanzee sample is indicated. The dominant HVR sequence in the chimpanzee is most closely related to a minor quasispecies that represents 3.83% of the HVR sequences in the patient, with 67% amino acid sequence homology between the 2.