Antibody-Dependent Enhancement of Hepatitis C Virus Infection

Meyer, Keith; Ait-Goughoulte, Malika; Keck, Zhen–Yong; Foung, Steven K. H.; Ray, Ranjit

doi:10.1128/jvi.01867-07

Cited by 37 publications

(34 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Abs from many chronically HCV-infected patients or persons vaccinated with experimental vaccines were shown to bind to HCV envelope glycoproteins without neutralizing infection (31,32). Some human serum and monoclonal Abs were even found to enhance HCV/vesicular stomatitis virus-pseudotype infections (40,41). Accordingly, although other models (48) consider immune stimulation and neutralization matrices U and V as being identical, the model developed here assumes that V and U differ, with v i,j ≥ u j,i ; i.e., the stimulation of an Ab response to j by i is more probable than neutralization of i by an Ab to j.…”

Section: Discussionmentioning

confidence: 99%

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Skums

Bunimovich

Khudyakov

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hepatitis C virus (HCV) has the propensity to cause chronic infection. Continuous immune escape has been proposed as a mechanism of intrahost viral evolution contributing to HCV persistence. Although the pronounced genetic diversity of intrahost HCV populations supports this hypothesis, recent observations of long-term persistence of individual HCV variants, negative selection increase, and complex dynamics of viral subpopulations during infection as well as broad cross-immunoreactivity (CR) among variants are inconsistent with the immune-escape hypothesis. Here, we present a mathematical model of intrahost viral population dynamics under the condition of a complex CR network (CRN) of viral variants and examine the contribution of CR to establishing persistent HCV infection. The model suggests a mechanism of viral adaptation by antigenic cooperation (AC), with immune responses against one variant protecting other variants. AC reduces the capacity of the host's immune system to neutralize certain viral variants. CRN structure determines specific roles for each viral variant in host adaptation, with variants eliciting broad-CR antibodies facilitating persistence of other variants immunoreacting with these antibodies. The proposed mechanism is supported by empirical observations of intrahost HCV evolution. Interference with AC is a potential strategy for interruption and prevention of chronic HCV infection.hepatitis C | viral quasispecies | cross-immunoreactivity | complex network | intrahost adaptation H epatitis C virus (HCV) causes chronic infection in ∼ 70% of infected people, who become at risk for developing severe liver diseases (1). The virus establishes chronic infection by using several molecular mechanisms for averting innate immunity and attenuating effectiveness of adaptive immune responses (2). HCV is one of the most heterogeneous viruses infecting humans and exists in each infected host as a population of genetically related variants (3, 4). Substantial heterogeneity and drastic changes in genetic composition of the intrahost HCV population observed during chronic infections have been interpreted as evidence of a continuous immune escape via random mutations, thereby generating increasing genetic diversity of viral populations in infected individuals (5-7).The observed cross-immunoreactivity (CR) of HCV variants from earlier stages of infection with antibodies (Abs) from later stages and ineffectiveness of Abs to immunoreact with variants from the same stage of infection (7) seemingly support the hypothesis of immune escape as a mechanism of intrahost evolution that contributes to establishment of persistent infections. However, several recent observations are incompatible with this hypothesis. First, the intrahost HIV population diversifies and diverts continuously from acute state to chronic infection until, at the onset of immunodeficiency, it starts losing heterogeneity and eventually stops diverting (8). Surprisingly, a similar temporal pattern of diversity and diversion was observed for intraho...

show abstract

Section: Discussionmentioning

confidence: 99%

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Skums

Bunimovich

Khudyakov

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, the reduction in selection intensity over the course of HCV infection is clearly attributable to the decline in specific immune responses. Although molecular mechanisms responsible for the decline in the immune pressure on HCV HVR1 at late stages of infection are not known, it can be speculated that such an intrahost environment is caused by B-cell dysfunctions, such as those leading to the hyperactivity and exhaustion observed during chronic HIV (29) and HCV (43) infections; may be related to or associated with competition between antigenic sites (55), a paucity of high-affinity immune cell receptor recognition (54), the "original-antigenic-sin" response (11,22), or the enhanced antibody-dependent uptake of some HCV variants (28); or may be the result of a combination of these conditions.…”

Section: Discussionmentioning

confidence: 99%

Temporal Variations in the Hepatitis C Virus Intrahost Population during Chronic Infection

Ramachandran

Campo

Dimitrova

et al. 2011

J Virol

View full text Add to dashboard Cite

The intrahost evolution of hepatitis C virus (HCV) holds keys to understanding mechanisms responsible for the establishment of chronic infections and to development of a vaccine and therapeutics. In this study, intrahost variants of two variable HCV genomic regions, HVR1 and NS5A, were sequenced from four treatment-naïve chronically infected patients who were followed up from the acute stage of infection for 9 to 18 years. Median-joining network analysis indicated that the majority of the HCV intrahost variants were observed only at certain time points, but some variants were detectable at more than one time point. In all patients, these variants were found organized into communities or subpopulations. We hypothesize that HCV intrahost evolution is defined by two processes: incremental changes within communities through random mutation and alternations between coexisting communities. The HCV population was observed to incrementally evolve within a single community during approximately the first 3 years of infection, followed by dispersion into several subpopulations. Two patients demonstrated this pattern of dispersion for the rest of the observation period, while HCV variants in the other two patients converged into another single subpopulation after ϳ9 to 12 years of dispersion. The final subpopulation in these two patients was under purifying selection. Intrahost HCV evolution in all four patients was characterized by a consistent increase in negative selection over time, suggesting the increasing HCV adaptation to the host late in infection. The data suggest specific staging of HCV intrahost evolution.Hepatitis C virus (HCV) infection is a major cause of liver disease in the world. It is estimated that ϳ130 million people are infected with HCV globally (2). HCV is a heterogeneous single-stranded (plus-strand) RNA virus belonging to the Flaviviridae. The HCV genome contains one large open reading frame that encodes a polyprotein which can be processed into 10 mature proteins (34). HCV causes chronic infection in 70 to 85% of infected adults. There is no vaccine against HCV, and current antiviral therapy is effective in only 50 to 70% of chronically infected patients (18).HCV intrahost evolution is frequently compared to an "arms race," implying that the HCV genome constantly changes in order to escape from neutralizing adaptive immunoresponses (53). This concept of constant change is seemingly different from the HIV model, according to which intrahost evolution slows down with CD4 ϩ T-cell depletion and quasispecies diversity decreases with the development of AIDS (48). Our limited understanding of the dynamics of HCV intrahost evolution impedes the development of efficient therapeutic and prophylactic interventions.Analysis of HCV longitudinal evolution is significantly hindered by difficulties with identifying and with long-term follow-up of patients, starting from the acquisition of infection. In the present study, we explored HCV evolutionary processes during long-term chronic infection in four treatment-...

show abstract

“…(50). FcR-mediated enhancement of HCV infection has been proposed previously (36), and it is possible that this mechanism will enhance infectivity into hepatocytes. Alternatively, FcR-independent enhancement might arise through the antibody-mediated dimerization of viral glycoproteins, as has been reported for HIV-1 gp120 (51).…”

mentioning

confidence: 99%

Hepatitis C Patient-Derived Glycoproteins Exhibit Marked Differences in Susceptibility to Serum Neutralizing Antibodies: Genetic Subtype Defines Antigenic but Not Neutralization Serotype

Tarr

Urbanowicz

Hamed

et al. 2011

J Virol

View full text Add to dashboard Cite

Neutralizing antibodies have a role in controlling hepatitis C virus (HCV) infection.A successful vaccine will need to elicit potently neutralizing antibodies that are capable of preventing the infection of genetically diverse viral isolates. However, the specificity of the neutralizing antibody response in natural HCV infection still is poorly understood. To address this, we examined the reactivity of polyclonal antibodies isolated from chronic HCV infection to the diverse patient-isolated HCV envelope glycoproteins E1 and E2 (E1E2), and we also examined the potential to neutralize the entry of pseudoparticles bearing these diverse E1E2 proteins. The genetic type of the infection was found to determine the pattern of the antibody recognition of these E1E2 proteins, with the greatest reactivity to homologous E1E2 proteins. This relationship was strongest when the component of the antibody response directed only to linear epitopes was analyzed. In contrast, the neutralization serotype did not correlate with genotype. Instead, serum-derived antibodies displayed a range of neutralization breadth and potency, while different E1E2 glycoproteins displayed different sensitivities to neutralization, such that these could be divided broadly into neutralization-sensitive and -resistant phenotypes. An important additional observation was that entry mediated by some E1E2 proteins was enhanced in the presence of some of the polyclonal antibody fractions isolated during chronic infection. These data highlight the need to use diverse E1E2 isolates, which represent extremes of neutralization sensitivity, when screening antibodies for therapeutic potential and for testing antibodies generated following immunization as part of vaccine development.

show abstract

Antibody-Dependent Enhancement of Hepatitis C Virus Infection

Cited by 37 publications

References 67 publications

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Antigenic cooperation among intrahost HCV variants organized into a complex network of cross-immunoreactivity

Temporal Variations in the Hepatitis C Virus Intrahost Population during Chronic Infection

Hepatitis C Patient-Derived Glycoproteins Exhibit Marked Differences in Susceptibility to Serum Neutralizing Antibodies: Genetic Subtype Defines Antigenic but Not Neutralization Serotype

Contact Info

Product

Resources

About