Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon‐free treatment era

Abstract

The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.

A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections

“…The quest for an understanding of the outcomes of viral infections has led, over the years, to the identification of an array of factors, including the size of the viral inoculum (5), the innate and NK cell responses (6,30), and host genetic variations (13), that can potentially influence the outcomes. Here, we argue that underlying the effects of these factors is an essential dynamical motif, comprising the key interactions between antigens and CD8 T cells, that governs the outcomes.…”

“…We considered a realization of the latter phenomenon next, in the spontaneous clearance of HCV infection. (29,30). It is also known to require strong CD8 T cell responses (31).…”

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

“…Synergy could arise from the effects of the drugs at the single cell level (Gupta and Dixit, 2018;Jilek et al, 2012;Padmanabhan et al, 2014) or at the cell population level (Padmanabhan et al, 2014;Raja et al, 2018;Venugopal et al, 2018). We sought to examine first whether synergy could arise in our calculations from effects at the single cell level.…”

Introduction to modeling viral infections and immunity

“…11 On the other hand, the clinical care of HCV has seen an enormous transformation, where DAAs are able to cure a large fraction of infected patients with treatments that typically last 12 weeks or less. Although these have been very successful, there may be scope for improving protocols and Raja et al 12 The two reviews that follow deal with Mycobacterium tuberculosis (Mtb) and malaria. These are two very good examples of how the ideas of viral dynamics may be applied to pathogens that are potentially more complex in their life cycles, and (as in these cases) that have thwarted our efforts to control them for millennia.…”

“…On the other hand, the clinical care of HCV has seen an enormous transformation, where DAAs are able to cure a large fraction of infected patients with treatments that typically last 12 weeks or less. Although these have been very successful, there may be scope for improving protocols and Raja et al discuss the role of interferon in HCV treatment with DAAs. Here, it is clear that understanding the ongoing innate immune response may be critical to designing better treatment protocols.…”