HCV adapts to host immune response and DAAs
Posted on April 25, 2015
HCV is a rapidly evolving virus with a high mutation rate: adaptation to the host immune response and selection of HCV strains resistant to direct-acting antiviral therapies
Hepatitis C virus (HCV) is a positive strand-enveloped ribonucleic acid (RNA) virus, and the single-stranded RNA molecule consists of a large open reading frame encoding a polyprotein precursor of approximately 3,000 residues, which is processed during and after translation into three structural proteins (core protein and the envelope proteins E1 and E2), a small viroporin protein p7, and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The NS5B protein is an RNA-dependent RNA polymerase that lacks 3′-5′ exonuclease proofreading activity, resulting in a high rate of mutations in viral progeny.
Evolutionary forces, such as random genetic drift and selection, affect the frequency of these mutations in the circulating HCV strains. These changes may affect the virus at different levels, including replicative fitness, pathogenicity, immune escape, and response to viral treatment. In a review article recently published in the journal Infection and Drug Resistance, Anne Plauzolles and colleagues discuss the “state of play” on viral escape mutations to host T-cell responses in the context of the hepatitis C virus, and their influence on infection outcome (Plauzolles A et al. Infect Drug Resist. 2015 Apr 7;8:63-74: this review article is freely available from the PubMed Collection). Knowledge of viral adaptation to the different arms of the host’s immune response will be useful in the design of a preventative vaccine for HCV, as well as in identifying new treatment strategies.
The interplay of several viral and host factors influences HCV-infection outcome, and the authors note that “the host’s immune response is an important correlate of infection outcome”. The first line of defense against an infection is the host’s innate immune response. The authors discuss how this primary response relies on the following strategies: “microbial-nonself” and “missing-self” identification. The missing-self strategy relies on the recognition by natural killer (NK) cells of lost expression during infection of human leukocyte antigen (HLA) class I molecules, which are typically expressed exclusively on normal healthy cells. NK cells, which have a crucial role in the fight against viral infections as part of the innate immune system, identify and lyse these infected target cells. While downregulation of HLA class I molecules on virally infected cells is thought to be an immune evasion strategy utilized by viruses against cytotoxic CD8+ T cells, which are reliant on the recognition of viral peptides in complex with HLA class I, these cells do become susceptible to missing-self recognition by NK cells.
Microbial nonself identification is the first pattern-recognition strategy. This process is based on the recognition of molecular structures that are not produced by the host, but are common within microorganisms. Viruses such as HCV produce viral pathogen-associated molecular patterns (PAMPs). These PAMPs act as a “molecular signature” of the infecting microbial organism, and are able to initiate a cascade of events leading to innate intracellular immunity, with the production of antimicrobial effectors and proinflammatory and antiviral cytokines (eg, IFN, TNF, IL-1), as well as the production of gene products that prime the adaptive immune responses. Stimulation of antigen-specific, adaptive immune responses to viral pathogens typically follows the activation of the innate immune system. Authors note that “clearance of HCV seems to require a rapid and effective adaptive immune response targeting multiple antigenic targets of the virus polyprotein”. An individual experiencing a self-limited course of HCV infection will generally have a vigorous, broad, and sustained CD4+ and CD8+ T-cell response directed against HCV.
Authors also note that impairment of cellular immune responses is a recurrent factor among chronic HCV-infected individuals. Progression to chronicity among infected individuals may be due to either weak or stunted T-cell responses developed by the host and/or immune escape. HCV has developed several strategies to combat the host’s immune response, and these strategies involving protein–protein interactions and specific mutations within the virus to escape recognition by the immune system, are discussed in detail in this review article.
Interestingly, the authors discuss how in addition to immune selective pressure, antiviral treatment is another factor that can influence within-host viral diversity. Unlike interferon, the new direct-acting antiviral (DAA) drugs used for hepatitis C do not enhance existing immune responses, but directly target the action of viral proteins involved in the virus’s life cycle. While DAA drugs are more effective and tolerable than interferon-based regimens, the authors caution that HCV is a rapidly evolving virus with a high mutation rate. The rapid emergence of drug-resistance mutations could jeopardize treatment outcomes with DAA drugs, and represents a viral escape mechanism not associated with interferon-based therapies. Authors of this review article note the following: In parallel to DAAs, agents targeting host proteins or nucleic acids are being developed. These compounds target cellular proteins and microRNAs that are essential for the viral life cycle, and thus inhibit the ability of HCV to use host-cell components for continued infection. These pharmaceutical agents include cyclophilin inhibitors, which aim to disrupt the interaction of NS5a and cyclophilin A, and an antagonist of microRNA 122 that inhibits its binding to the 5′ untranslated region of the HCV genome, an essential step for HCV replication. These agents could be an important addition to DAAs in the treatment of HCV, as they have a high genetic barrier to resistance, with no cross-resistance with DAAs and present pan-HCV genotypic activity.