Exposure to Hepatitis C Virus Induces Cellular Immune Responses Without Detectable Viremia or Seroconversion

Abstract

Sporadic cases of cell-mediated immunity (CMI) in persons exposed to hepatitis C (HCV) but evidently uninfected have been reported. To further define this, we measured CMI in individuals without evidence of HCV infection, that is, negative for HCV-antibodies (anti-HCV) and RNA, residing in a rural Egyptian community where prevalence of anti-HCV was 24%. Cell-mediated immunity (CMI) measured by interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay, confirmed by intracellular staining using flow cytometry, against HCV peptides was measured in seronegative individuals with high-risk (HR) and low-risk (LR) exposures to HCV. Thirteen of 71 (18.3%) HR subjects but only 1 of 35 (2.9%) LR subjects had detectable CMI (P = 0.032). These data are compatible with the hypothesis that exposures to HCV may lead to development of HCV-specific CMI without anti-HCV and ongoing viral replication. We speculate induced CMI clears HCV sometimes when anti-HCV is not detectable, and HCV-specific CMI is a useful surrogate marker for exposure to HCV.

Trace amounts of sporadically reappearing HCV RNA can cause infection

“…Thus, the final testing for HCV RNA and HCV antibodies should occur more than 7 months after exposure, which is a longer follow-up than currently recommended by the Centers for Disease Control and Prevention (CDC) (17). The presence of T cell responses in the absence of viremia and seroconversion in the 3 experimental chimpanzees is reminiscent of the immune status of subgroups of injection drug users, health care workers, and family members of chronic HCV patients who are frequently exposed to low-level HCV but test negative for HCV RNA and antibodies (24)(25)(26)(27)(28)(29)(30). Of note, however, there was no substantial increase in the breadth or strength of the immune response after each exposure, which is consistent with attrition of memory T cell subpopulations after heterologous exposures (31,32) and with the observation that the T cell responses of the lowdose HCV-exposed chimpanzees did not protect against highdose HCV challenge (33).…”

Hepatitis C Virus-Multispecific T-Cell Responses without Viremia or Seroconversion among Egyptian Health Care Workers at High Risk of Infection

“…In these HCV-seronegative aviremic subjects, HCV-specific CMI is the only biomarker of host exposure to the virus and may provide protection against chronic infection (38). In this regard, HCV-specific T-cell responses have been demonstrated without viremia or seroconversion in individuals exposed to HCV infection, such as family members living with two or more HCV-infected subjects (3), sexual contacts of acute HCV patients (24), intravenous drug users (37,52), and health care workers (HCW) after needle stick injury (29). These data support the view that host immune responses may determine the course of the disease (3).…”

“…Recent reports have documented sporadic cases of detectable HCV-specific CMI in exposed uninfected persons (3,17,24,29,37,39,41,52) without evidence of persistent infection, i.e., without viremia or seroconversion. In these HCV-seronegative aviremic subjects, HCV-specific CMI is the only biomarker of host exposure to the virus and may provide protection against chronic infection (38).…”

Acute hepatitis C virus infection: A chronic problem

“…56 In fact, there exists a subpopulation of individuals exposed to HCV that clear the virus without the induction of anti-HCV antibodies; therefore, the only surrogate markers for HCV exposure in such persons are HCV-specific cell-mediated immune responses. [57][58][59][60][61][62][63] …”