Sequence evolution and cross‐reactive antibody responses to hypervariable region 1 in acute hepatitis C virus infection*

Abstract

Hepatitis C virus (HCV) infection may result in acute resolving or chronic infection. Patients that clear the infection have a more vigorous cellular immune response and an early humoral response to the hypervariable region 1 (HVR1) of the E2 envelope protein. To analyse further the properties of the early anti-HVR1 response, cross-reactivity of anti-HVR1 responses was assessed in five patients with acute HCV infection, who were infected by the same virus strain during a nosocomial outbreak. The sequence evolution of HVR1 was examined in sequential serum samples up to 37 months post infection. Peptides were synthesised corresponding to the obtained HVR1 sequences and unrelated HVR1 sequences, and antibody reactivity to the peptides in sequential sera was investigated by ELISA. The results suggest an association between specific gaps in humoral immunity and the HVR1 sequence evolution during early infection. Possible interpretations of this phenomenon include immune escape mechanisms or suppression of specific anti-HVR1 antibodies.

Hepatitis C Virus Antigenic Convergence

“…To overcome this problem, many groups have used mice to study the immune response to the HVR1 epitope262728. Several studies have shown the specific reactivity of HVR1 peptides with sera of infected individuals26272930313233. We modeled HVR1 CR using serum specimens from mice immunized with 103 synthetic peptides representing different HVR1 variants (referred to as immunogens).…”

Evaluation of cross-reactive antibody response to HVR1 in chronic hepatitis C

“…It has been reported that the anti-HVR1 antibodies in HCV infected individuals could react with more than one variant of HVR1 [15,16,22] . In this study, 16 representative HVR1 antigens distributed homogeneously were used to evaluate the cross-reactivity of HVR1 antibodies.…”

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“…Although an early anti-HVR1 response is associated with self-limiting acute infection [13] , anti-HVR1 antibodies are frequently produced in the majority of chronically infected individuals and appear to coexist with the HVR1 variants [14] . In most instances, the sera of HCV infected patients are frequently cross-reactive with unrelated HVR1 sequences [15,16] . However, the cross-reactive nature of anti-HVR1 responses and the relationship between the cross-reactivity and the progression of hepatitis are largely unknown.…”

Immunopathogenesis of Hepatitis C Virus Infection

“…However, chimpanzee cross-challenge experiments (152, 258–266) and human series (267) show that HCV-specific antibodies do not universally mediate protection. Possible reasons for the lack of antibody-mediate protection include: 1) the mutable quasispecies nature of HCV with rapid selection of antibody escape variants (253, 268); 2) intrinsic sequence specific variability of the sensitivity of E1E2 proteins to neutralization (269, 270); and 3) paradoxical facilitation of viral entry by “neutralizing” antibodies (269, 271). In up to 40% of patients with spontaneous viral clearance, HCV antibody titers may wane after 2–3 decades (272).…”