Innate and Adaptive Immune Regulation During Chronic Viral Infections

Abstract

Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8(+) T cell functions, and specialization of CD4(+) T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.

Keywords: HCV; HIV; LCMV; T cells; chronic viral infection; interferon.

Figure 1

Type I interferon (IFN-I) dynamics and opposing effects during chronic viral infections. Upon infection with most persistent viruses, IFN-I are powerfully and systemically induced; this initial response is rapidly attenuated, although low IFN-I and IFN-I-stimulated gene (ISG) levels still persist in multiple cells and tissues. Several innate cells, including macrophages, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs) (and possibly nonhematopoietic cells, which are not depicted), sense viral products via pattern-recognition receptors (PRRs) to contribute to IFN-I levels. Although they are the most powerful IFN-I producers early after challenge with persistent viruses, pDCs show an impaired capacity to produce IFN-I during chronic stages of lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections. IFN-I exert both beneficial and detrimental effects on immune responses and viral control, which appear conserved among different persistent infections. The relative degree and impact on viral replication of such opposing IFN-I effects may vary for individual cases.

Figure 2

CD4⁺ and CD8⁺ T cell adaptation during chronic viral infections. Persistent antigen drives recalibration of T cell responsiveness by inducing transcriptional (e.g., reduced TBET and increased EOMES), epigenetic (e.g., DNA methylation of the PD1 gene locus), and metabolic (e.g., reduced glycolysis and spare respiratory capacity) changes that result in limited functional properties [e.g., CD8⁺ T cell cytotoxicity, T helper 1 (Th1) cytokine production] and/or functional specialization [e.g., IL-21 elevation and T follicular helper (T_FH) cell differentiation]. Recent studies have begun uncovering the heterogeneity in the CD4⁺ and CD8⁺ T cell compartment during chronic viral infection. Importantly, although they are partially hyporesponsive, CD4⁺ and CD8⁺ T cells are essential to control persistently replicating viruses in mice and humans.