Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C Virus Infection

Abstract

There are 257 million persons worldwide with chronic hepatitis B virus (HBV) infection, a leading causes of liver cancer. Almost all adults with acute HBV infection have a rapid immune response to the virus, resulting in life-long immunity, but there is no cure for individuals with chronic HBV infection, which they acquire during early life. The mechanisms that drive the progression of HBV through distinct clinical phases to end-stage liver disease are poorly understood. Likewise, it is not clear whether and how immune responses can be modulated to allow control and/or clearance of intrahepatic HBV DNA. We review the innate and adaptive immune responses to acute and chronic HBV infections and responses to antiviral therapy. Comparisons with hepatitis C virus infection provide insights into the reversibility of innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses.

Keywords: Hepatitis B Virus; Hepatitis C Virus; Immune Memory; Innate.

Figure 1.. Acute, Self-limited HBV and HCV infection and Chronic HBV Infection

(A, B) Studies of acute, self-limited HBV and HCV infection provide information about successful immune responses. (A) HBV DNA is detectable within the first 2 months of infection and its peak precedes the onset of T-cell responses and the increase in serum level of ALT. (B) HCV RNA becomes detectable within a few weeks after infection and is associated with the induction of ISGs. T-cell responses occur after 8–12 weeks in most patients concomitant with a surge in serum ALT levels. Neutralizing antibodies (nAb) against HCV become detectable a few weeks later. (C) Phases of chronic HBV infection: the immune-tolerant phase is characterized by high levels of HBV DNA and HBsAg and a normal level of ALT. In the immune-clearance phase and the HBeAg⁺ chronic hepatitis phase, levels of HBV DNA and ALT decrease and the level of ALT increases, indicating liver injury. The transition between the first 2 phases of disease can be dynamic and associates with repeated increases and decreases in level of HBV DNA and activity of ALT (indicated by the dashed lines). This phase can ultimately lead to HBeAg seroconversion. The subsequent inactive carrier state is characterized by low levels of HBV and HBsAg and a normal level of ALT, but reactivation in the HBeAg-negative chronic hepatitis phase is associated with flares in levels of ALT and ongoing liver disease.

Figure 2.. Phenotypic, Transcriptional, and Tunctional Properties of Virus-specific CD8+ T Cells

(A) Exhausted CD8⁺ T cells are characterized by high expression of exhaustion markers and the transcription factor eomesodermin and an impaired capacity to produce cytokines or proliferate. Memory-like CD8⁺ T cells have features of exhausted cells (PD1 expression) and memory cells (expression of the IL7 receptor CD127 and the transcription factor TCF1). Their functional properties are increased in comparison to exhausted cells but impaired in comparison to memory cells. Memory CD8⁺ T cells express low levels of exhaustion markers, have recall effector functions, and express the transcription factors T-box 21 (TBX21 or TBET) and HNF1 homeobox A (HNF1A or TCF1).(B) Virus-specific memory-like CD8⁺ T cells sustain the T-cell response during chronic infection (modified from with permission).

Figure 3.. Changes in HCV-specific T-cell Subsets During and After DAA Therapy

During chronic HCV infection, the 2 subsets of PD1⁺ HCV-specific CD8⁺ T cells are severely exhausted T cells and memory-like T cells. After successful DAA therapy, higher numbers of memory-like CD8⁺ T cells are maintained due to their antigen-independent proliferative capacity while severely exhausted, antigen-dependent CD8⁺ T cells decrease in number. This is reflected by an improved proliferative capacity of the overall HCV-specific CD8⁺ T-cell population.