Trace amounts of sporadically reappearing HCV RNA can cause infection
Naga Suresh Veerapu, Su-Hyung Park, Damien C. Tully, Todd M. Allen, Barbara Rehermann
Naga Suresh Veerapu, Su-Hyung Park, Damien C. Tully, Todd M. Allen, Barbara Rehermann
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3469-3478. doi:10.1172/JCI73104.
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Categories: 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 1

Clinical follow-up of chimpanzees that remained aviremic after infusion of human plasma and PBMCs.

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Clinical follow-up of chimpanzees that remained aviremic after infusion ...
(A) Chimpanzee A3A025 was intravenously infused at weeks 0, 9, and 18 with HCV RNA– negative plasma and at week 27 with HCV RNA–negative PBMCs from anti-HCV–negative blood donors. Each infused sample was derived from a different blood donor (Table 1). (B) Chimpanzees A3A015 and A3A017 were 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 below the detection limit of the qualitative COBAS Amplicor HCV Test 2.0. Each infused sample was derived from a different patient (Table 1 and ref. 8). The presence of HCV RNA was assessed in blood and liver by qualitative RT-PCR. Intrahepatic expression of the ISG OAS1 was quantitated by real-time PCR. Intrahepatic IFIT1, MX1, CXCL10, CXCL11, CD8B, and IFNG mRNA levels were also quantitated by real-time PCR and did not increase over time (not shown). The 4 arrows in each graph indicate the 4 time points at which chimpanzees were infused with the biospecimens. The dotted blue line indicates the upper limit of normal of ALT levels.