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
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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 5

HCV-specific humoral and cellular immune responses of the infused chimpanzees.

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HCV-specific humoral and cellular immune responses of the infused chimpa...
Chimpanzee A3A025 was intravenously infused at weeks 0, 9, and 18 with plasma and at week 27 with PBMCs from anti-HCV–negative and HCV RNA–negative blood donors. Chimpanzees A3A015, A3A017, and A3A013 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). The 4 small arrows in each graph indicate the 4 time points at which the chimpanzees were infused with human specimens. (A) Plasma samples were tested using Ortho ECi Vitros for HCV core, NS3, NS4, and NS5 antibodies. An anti-E2 EIA was performed as previously described (41). “–” indicates undetectable antibodies against HCV E2 of genotypes 1a and 1b. Shaded area indicates the HCV titer in the blood. (B) HCV-specific T cell responses were assessed by stimulating PBMCs with 18 pools of overlapping HCV peptides and quantitating TNF-α, CCL4, CXCL9, and CXCL10 in the cell culture supernatant using a cytometric bead array assay. (C) Summary of HCV-specific antibody and T cell responses. Black squares indicate an immune response above the cutoff, and white squares indicate an absence of an immune response.