Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections

Abstract

Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained. The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted.

Figure 1.

Adaptive immunity in hepatitis A virus (HAV) infection. (A) Typical hepatitis A. The majority (>90%) of acute HAV infections are characterized by an incubation phase of 3–4 weeks followed by an icteric phase of 2–4 weeks (see Shin and Jeong 2018). Hepatitis, which is thought to be immune mediated, is highly variable in severity. It ranges from clinically inapparent in young children to more severe in older children and adults. Serum anti-HAV IgM antibodies appear within a few days of the onset of hepatitis and generally become undetectable within 4 months. Anti-HAV IgG antibody titers increase in the late symptomatic phase and remain detectable for life. HAV-specific CD8⁺ T cells have been detected in blood and liver of patients during the icteric phase (Vallbracht et al. 1986, 1989; Fleischer and Vallbracht 1991; Schulte et al. 2011), and probably decline in frequency with resolution of the infection (Schulte et al. 2011). Recent studies have also described expansion of innate cytotoxic cells and T regulatory (Treg) cells that have converted to an inflammatory phenotype in individuals with symptomatic infections (Choi et al. 2018b; Kim et al. 2018). CD4⁺ and CD8⁺ T-cell frequency and function have been described in too few studies to superimpose kinetic curves on the profile of resolving HAV infections. Key unanswered questions about adaptive immune responses in acute hepatitis A are shown to the right. (B) Relapsing hepatitis A. Approximately 5%–10% of acute HAV infections relapse about 1–4 months after apparent resolution of symptoms and virus replication. Very little is known about adaptive immune responses in this uncommon but fascinating atypical form of the infection. Anti-HAV IgM responses persist through the relapse phase, and therefore are sustained for a longer period of time when compared with typical infections that do not relapse. Little is known about the anti-HAV IgM response or the nature of T-cell immunity during the primary or relapsing phases of infection. It is likely that failure to develop or sustain a virus-specific humoral or cellular immune response facilitates relapse of infection. It is important to emphasize that even relapsing infections eventually resolve, and persistence of HAV has not been described under conditions that lead to chronic hepatitis E virus (HEV) infection.

Figure 2.

Adaptive immunity in hepatitis E virus (HEV) infection. (A) Typical hepatitis E. The course of acute HEV infection is very similar to that described for hepatitis A virus (HAV) infection. An incubation phase of 3–4 weeks can be followed by a period of overt hepatitis that persists for about an additional 2–4 weeks (see Aggarwal and Goel 2018). However, many HEV infections in adults are clinically inapparent, especially those caused by genotype 3 viruses. The anti-HEV antibody profile is also similar to HAV infection, with an early IgM response that transitions to an IgG isotype during the later stages of acute infection. The IgG response is typically durable after convalescence, but there is evidence that titers fall below protective thresholds in some patients who are susceptible to reinfection. How commonly seroreversion occurs and whether the severity and duration of second infections is reduced is not yet known. HEV-specific CD8⁺ T-cell activity has been detected in the blood of infected patients who had symptoms of acute infection (Suneetha et al. 2012; Brown et al. 2016). Whether expansion of functional cytotoxic CD8⁺ T cells is temporally associated with control of virus replication or the timing and severity of liver disease remains to be determined. To date there has been no analysis of other cytotoxic cell populations during acute infection, including those of the innate lineage, as has been described for HAV. Importantly, it is not yet known whether antibodies contribute to resolution of infection with this quasi-enveloped virus and is somewhat difficult to predict because there is as yet no positive demonstration that passive transfer of anti-HEV antibodies during the incubation phase of infection will prevent or temper hepatitis. The minimum humoral or cellular responses required to prevent HEV persistence have not yet been identified. Key unanswered questions about adaptive immune responses in acute hepatitis E are summarized to the right of the panel. (B) Persistent hepatitis E. HEV infection persistence has been described in individuals with compromised immunity caused by hematological malignancies, organ allograft, and HIV coinfection. HEV-specific T-cell responses are clearly reduced or undetectable in these patients (Suneetha et al. 2012; Brown et al. 2016), but appear to strengthen at least transiently with resolution of infection (Suneetha et al. 2012). The timing and magnitude of anti-HEV IgM and IgG responses in chronically infected patients is highly variable and difficult to generalize; persistence of HEV in the absence of seroconversion has been described in some patients, while others do develop detectable IgM and/or IgG responses (Pas et al. 2012; Kamar et al. 2013; Moal et al. 2013). Studies in solid organ transplant recipients demonstrated that IgM seroconversion can take months to develop, and the IgM response appears to persist throughout chronic infection (Legrand-Abravanel et al. 2010; Choi et al. 2018a).