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 2

Clinical and virological follow-up of chimpanzee A3A013 that developed systemic viremia after infusion of human plasma and PBMCs.

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Clinical and virological follow-up of chimpanzee A3A013 that developed s...
Chimpanzee A3A013 was intravenously infused at weeks 0, 9, and 18 with plasma and at week 27 with PBMCs from anti-HCV–positive patients with trace amounts of HCV. Each infused sample was derived from a different patient (Table 1 and ref. 8). The 4 arrows indicate the 4 infusion time points. (A) The presence of HCV RNA was assessed in blood and liver by qualitative nested RT-PCR. – and + symbols indicate HCV RNA–negative and –positive samples, respectively. Serum HCV RNA levels, serum ALT levels, and intrahepatic OAS1 mRNA levels are indicated with a red line, a blue line, and a green area, respectively. The dotted blue line indicates the upper limit of normal of ALT levels. (B) Intrahepatic IFIT1, MX1, CXCL10, CXCL11, CD8B, and IFNG mRNA levels were determined by real-time PCR, normalized to endogenous references, and expressed as fold induction over week-0 values.