Protective immunity against hepatitis C: many shades of gray

Abstract

The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.

Keywords: HCV reinfection; NK cells; T cells; acute infection; adaptive immunity; antibodies; hepatitis C; innate immunity.

Figure 1

HCV genome and polyprotein. The HCV genome is composed of an open reading frame (ORF) flanked by 5’ and 3’ untranslated regions (UTRs). IRES-mediated translation of the ORF leads to the formation of a polyprotein that is processed into 10 viral proteins. Cleavage of the core protein from E1 involves cellular signal peptidases, which also cleave E1, E2, and p7 from the polyprotein (pink arrows). The NS2–NS3 protease auto-cleaves itself (green arrow). The NS3 protease located in the first one-third of NS3, assisted by its membrane-bound cofactor, NS4A, cleaves the remaining proteins NS3, NS4A, NS4B, NS5A, and NS5B (violet arrows).

Figure 2

Summary of innate and adaptive immunity during primary HCV infection. (1) HCV entry and replication inside hepatocytes induces the production type I and type III IFNs that are also secreted by pDCs and create an antiviral state in infected hepatocytes and neighboring cells and stimulate NK cells that kill infected hepatocytes. (2) Liver resident and migratory APCs (Kupffer cells and DCs) uptake apoptotic bodies from destroyed HCV-infected hepatocytes and present HCV-derived epitopes to both CD4 and CD8 T cells in the context of MHC class II and MHC class I, respectively. (3) The cross-talk between DCs and NKs regulates the function of both cells enhancing antigen presentation and priming, as well as NK-mediated killing. (4) CD4 helper T cells support responses of CD8 T cells and B cells through production of Th1 and Th2 cytokine, respectively. (5) Whether Abs produced from B cells during primary infection have an essential role in viral clearance by directly neutralizing the virus or by mediating ADCC is not fully understood, and the role of Tfh cells in this process is still unknown. (6) CD8 T cells eliminate HCV-infected cells through direct cytotoxic mechanisms (cytolytic granules, as perforin and granzyme) or non-cytolytic mechanisms through secretion of the antiviral cytokines IFNγ and TNFα. (7) CD8 T cell functions are sustained and enhanced by IL-21 mainly produced by Th17 cells. IL-21 is also essential to rescue virus-specific T cells from exhaustion caused by persistent exposure to HCV antigens. Reduced IL-21 production or Th17 cell numbers results in an increased exhaustion status and expression of exhaustion markers like PD-1, Tim-3, CTLA-4, and others. (8) Regulatory T cells might be a cause in the failure of the primary immune response by secreting the regulatory cytokines TGFβ, IL-10, or secretion of Gal-9 that enhances apoptosis of Tim-3⁺ CD4 and CD8 T cells. ADCC, antibody-dependent cellular cytotoxicity; APC, antigen-presenting cell; CTLA-4, cytotoxic T lymphocyte antigen-4; DC, dendritic cell; FcR, receptor for the constant fragment of the antibody; Gal-9, galactin-9; Gz, granzyme; HCV, hepatitis C virus; IFN, interferon; IL, interleukin; NK, natural killer; PD-1, Programed death-1; pDC, plasmacytoid DC; Tfh, T follicular helper cells; TGF, transforming growth factor; Th17, T-helper 17 cell; Tim-3, T cell immunoglobulin and mucin domain 3; TNF, tumor necrosis factor; Treg, regulatory T cell.

Figure 3

Hypothetical model for protective and non-protective immunity upon HCV reinfection. Individuals who spontaneously clear primary HCV infection develop long-lived virus-specific memory CD4 and CD8 T cells. Such memory T cell populations are maintained by the action of homeostatic cytokines like IL-7, IL-15, and IL-21. Upon HCV reinfection, some individuals will be protected against viral persistence while others will be unprotected. (A) The protected individuals will be able to spontaneously clear the second infection with a shorter period of viremia and reduced peak viremia. Viral clearance will be accompanied by an accelerated memory T cell recall response detectable in both liver and blood. The exact characteristics of a protective response are yet to be defined in terms of breadth and quality. (B) In unprotected individuals, reinfection will be associated with a weak or late recall response and incomplete T cell-mediated control of viremia. The underlying causes of failure to resolve the reinfection despite the ability to spontaneously resolve a prior infection maybe low levels of homeostatic cytokines affecting the maintenance of memory T populations, reduced breadth, or quality of the recall response upon reinfection and increased frequency of Tregs leading to dampening of the immune response, viral persistence, and rapid exhaustion of HCV-specific T cells. Neutralizing antibodies, host genetics, and homology between the infecting viral sequences at different episodes may play a role in protection upon reinfection.