Hepatitis C Virus Antigenic Convergence

Campo, David S.; Dimitrova, Zoya; Yokosawa, Jonny; Hoang, Duc; Pérez, Nestor O.; Ramachandran, Sumathi; Khudyakov, Yury

doi:10.1038/srep00267

Cited by 25 publications

(32 citation statements)

References 55 publications

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“…The CRN was modeled as a scale-free network with a power-law degree exponent γ = 1.5 (according to ref. 19), using the Complex Networks Package (38). Viral variants and immune responses were assumed abolished once their values fell below their initial conditions.…”

Section: Resultsmentioning

confidence: 99%

“…HCV HVR1 variants can bind Abs obtained against genetically distant variants sharing only 20% of amino acid sites with the immunogen. Findings of the HVR1 antigenic diversity being extensively convergent and effectively limited (19) indicate frequent CR even among genetically distant HCV variants.…”

Section: Discussionmentioning

confidence: 99%

“…First, CR is known to be widespread among HCV HVR1 variants, with many of them showing a strict immune specificity and a fraction of the variants showing very broad CR (18,19,(26)(27)(28). It results in organization of CR among HVR1 variants in a complex, scale-free network (19).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike HIV, HCV lacks the ability to induce systemic immune suppression, suggesting a different mechanism of immune adaptation. Here, we develop a model that takes into consideration broad CR among viral variants (18,19,(26)(27)(28) and disparity between CR and neutralization (19,29). The model predicts antigenic cooperation (AC) among HCV variants that results in protection rather than continuous escape of the HCV population from the neutralizing Ab, thus suggesting a mechanism of intrahost evolution that leads to chronic infection.…”

Section: Significancementioning

confidence: 99%

“…Significant genetic variation of HVR1 during chronic infection was hypothesized to facilitate escape from neutralizing antibodies (17,18). However, recent genetic and immunological analyses showed that HVR1 antigenic diversity is extensively convergent and effectively limited, with HVR1 variants from different genotypes and subtypes being broadly cross-immunoreactive (19)(20)(21).…”

mentioning

confidence: 99%

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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.

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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...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%