Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease

Abstract

To define the early events that determine the outcome of acute hepatitis C virus (HCV) infection, we compared the course of viremia with the peripheral and intrahepatic T cell response and intrahepatic cytokine profile in six acutely infected chimpanzees. Three different outcomes were observed after peak viral titers were reached: sustained viral clearance, transient viral clearance followed by chronic infection, and chronic infection that persisted at initial peak titers. The results indicate that HCV spread outpaces the T cell response and that HCV rapidly induces but is not controlled by IFN-alphabeta; that viral clearance follows the entry and accumulation of HCV-specific IFN-gamma-producing T cells in the liver; and that it may not require the destruction of infected cells.

Fig 1.

Courses of acute HCV infection in chimpanzees after experimental inoculation with HCV. Quantitative HCV RNA levels were expressed as log GEs per milliliter of serum. HCV RNA was also monitored by in-house RT-nested PCR, and results are indicated as + or −. ALT activity was expressed as units per liter. HCV antibody responses reflect the results of an HCV EIA-2 assay as described in Materials and Methods. Liver biopsies were examined for necroinflammatory changes and scored as described (22).

Fig 2.

Peripheral and intrahepatic proliferative CD4+ T cell responses in acutely HCV-infected chimpanzees. The peripheral (A) and intrahepatic (B) responses to core, NS3, NS3–NS4, and NS5 are shown as the sum of all positive stimulation indices. If no response against any protein was detected, the sum was assigned a value of 2 to permit visualization of the results.

Fig 3.

Peripheral and intrahepatic CD8+ T cell responses in acutely infected chimpanzees. (A) Peripheral CD8+ T cell responses were tested against a large panel of HCV peptides (Table 2). The peptide-specific CD8+ T cell responses are shown at all time points tested, and they are expressed as the percentage of CD8+ T cells that produce IFN-γ in response to the respective peptides. (B) The intrahepatic CD8+ T cell response is shown as the percentage of intrahepatic CD8+ T cells that produce IFN-γ after stimulation with autologous B-LCL that were infected with recombinant vaccinia viruses vHCV 1–1488 or vHCV 827–3011, as described in Materials and Methods.

Fig 4.

Intrahepatic cytokine profiles in acutely HCV-infected chimpanzees. Liver RNA was tested for the expression of CD3, IFN-γ, and 2′5′ oligoadenylate synthetase. The L32 signal reflects the amount of RNA used in the assay.