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

Abstract

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...

Network Analysis of the Chronic Hepatitis C Virome Defines Hypervariable Region 1 Evolutionary Phenotypes in the Context of Humoral Immune Responses

“…Consequently, the minimum binding threshold required for virion neutralization is more difficult to achieve, which concomitantly facilitates the maintenance of related minor variants (54,55). Together, the data support a model of antigenic cooperation enabled in viromes, organized around a single dominant variant (51).…”

“…In the context of a convergent HVR1 variant pool, the presentation of successive, antigenically similar but nonidentical epitopes (Fig. 6E) may impart a cumulative weakening of the nAb response required for effective virion neutralization (51)(52)(53). Consequently, the minimum binding threshold required for virion neutralization is more difficult to achieve, which concomitantly facilitates the maintenance of related minor variants (54,55).…”

Analysis of Heterogeneous Genomic Samples Using Image Normalization and Machine Learning

“…As a result, RNA viruses exist in infected hosts as highly heterogeneous populations of genomic variants usually referred to as viral quasispecies. Intra-host and inter-host evolution of viral quasispecies is a complex phenomenon defined by dynamics of virulence, infectivity, drug resistance, immune escape, transmission rates, behavorial patterns and other phenotypic and epidemiological features, which plays crucial role in disease progression and outcome [1,5,7,26,30]. Challenges associated with understanding complex quasispecies evolution attracted many researchers in different domains, including virology, epidemiology, population genetics and systems biology.…”

“…High-throughput sequencing technologies and protocols are prone to errors and biases, which are especially pronounced for viral data. Indeed, frequencies of minor viral variants are often comparable with the level of sequencing noise; however, such variants should not be simply discarded based on some frequency threshold, since often they are the ones responsible for transmissions, immune escape or therapy failure [7,11,12,17,26,30]. Presence of sequencing errors introduces the noise to the data and produces outlier viral variants, which negatively affect the quality and accuracy of machine learning classifiers.…”

Accurate assembly of minority viral haplotypes from next-generation sequencing through efficient noise reduction

“…The composition and structure of intra-host viral populations plays a crucial role in disease progression and epidemic * Equal contributor † Corresponding authors, e-mails: {pskums, alexz}@cs.gsu.edu spread. In particular, low-frequency variants with few mutations with respect to dominant haplotypes may be responsible for viral transmission, immune escape, drug resistance, increase of virulence and infectivity [7,12,15,19,33,10,37].…”