How chronic viral infections impact on antigen‐specific T‐cell responses

Abstract

Persistent viral infections are, by definition, associated with ineffective antiviral immunity, in particular those infections caused by viruses that are highly productive and replicative (including HIV, HBV and HCV). The reasons for ineffective antiviral immunity in these types of infections are complex and manifold, and only recently a more comprehensive picture of the parameters responsible for attenuation of immune function is emerging. One reason for poor viral control in these types of infections is the functional deterioration of antiviral T-cell responses and understanding the underlying mechanisms is of key importance. This review summarizes our current knowledge of cell-intrinsic and cellextrinsic parameters that contribute to T-cell exhaustion during chronic viral infections and discusses related implications for host survival, immunopathology, and control of infection. Key words: Persistent viral infection . T-cell dysfunction . T-cell immunity IntroductionPersistent viral infections, by definition, are not entirely controlled by the host's immune system and are often associated with relevant clinical disease outcomes. Persistent viral infections can be roughly divided into (i) highly productive and replicative infections (associated with continued high abundance of viral antigens) and (ii) latent/reactivating infections (associated with low and perhaps sporadic levels of viral antigens). Well-known examples of the former are HIV, HBV and HCV, which together infect more than 2 billion people worldwide (http://www. unaids.org/; http://www.epidemic.org/; http://www.hepb.org/), and lymphocytic choriomeningitis virus (LCMV) infection in the mouse. Examples of the latter are herpes virus infections, including EBV, CMV, and HSV, which affect together almost 100% of the population. Viruses falling into these two categories have evolved very diverse strategies for co-existence in an immunocompetent host. Highly productive and replicative viruses tend to induce impaired virus-specific adaptive immune responses, which are characterized by limited and dysfunctional T-cell responses, and mutational escape from immune (or drug) pressure are common features of these viruses. Viruses causing latent/reactivating infections have, as a result of their large coding capacity, evolved strategies to interfere with host immunity (immune evasion mechanisms) and have acquired genetic programs that permit a latent, non-replicative existence of the viral genetic information with the option of resuming viral replication in response to certain stimuli. These viral reactivation events, however, are generally well controlled by host immunity and only become clinically apparent in circumstances of immunosuppression.This review focuses on highly productive and replicative persistent viral infections (hereafter referred to as persistent viral infection) with specific emphasis on cell-intrinsic and -extrinsic mechanisms responsible for constraining the size of the antiviral T-cell response and for T-cell dysfunction (summarized in Fig...

Host–virus interactions in hepatitis B and hepatitis C infection

“…In the search for an inducer of exhausted T cells, extensive studies have focused on PD-1 expression on HCV-specific CD8 ? T cells [98]. Urbani et al reported that the number of CD8 ?…”

Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

“…Moreover, we analyzed the expression levels of PD-1, Tim-3, and LAG-3 ( Fig. 2A), all of which are known to negatively regulate T-cell effector function during certain chronic infections with highly replicative viruses [19]. We have not observed any differences in expression levels of Tim-3 and LAG-3 on M25-specific CD4 + T cells compared with those of endogenous CD4 + T cells, with the exception of PD-1 being upregulated on M25-specific CD4 + T cells compared with endogenous CD4 + T cells in the lungs and iLNs.…”

Functional Exhaustion of CD4+ T Lymphocytes during Primary Cytomegalovirus Infection

“…Functional exhaustion of T cells is observed in patients with chronic hepatitis or HIV infection and is associated with increased expression of inhibitory receptors, in- cluding PD-1 and Tim-3 (26). To gain insight into the mechanisms regulating the function of CMV-specific CD4 + T cells, the expression of PD-1 and Tim-3 was measured at the level of CMV and TT-specific CD4 + T during primary and chronic infection.…”