Highly effective direct-acting antivirals against hepatitis C virus (HCV) have created an opportunity to transplant organs from HCV-positive individuals into HCV-negative recipients, since de novo infection can be routinely cured. As this procedure is performed more widely, it becomes increasingly important to understand the biological underpinnings of virus transmission, especially the multiplicity of infection. Here, we used single genome sequencing of plasma virus in 4 genotype 1a HCV-positive organ donors and their 7 organ recipients to assess the genetic bottleneck associated with HCV transmission following renal and cardiac transplantation. In all recipients, de novo infection was established by multiple genetically distinct viruses that reflect the full phylogenetic spectrum of replication-competent virus circulating in donor plasma. This was true in renal and cardiac transplantation and in recipients with peak viral loads ranging between 2.9–6.6 log10 IU/mL. The permissive transmission process characterized here contrasts sharply with sexual or injection-related transmission, which occurs less frequently per exposure and is generally associated with a stringent genetic bottleneck. These findings highlight the effectiveness of current anti-HCV regimens while raising caution regarding the substantially higher multiplicity of infection seen in organ transplantation–associated HCV acquisition.
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