The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)–infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-betloEomesloBlimp-1hiHobitlo T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69+CD103+ CXCR6+CXCR3+). These tissue-resident memory T cells (TRM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFβ induces liver-adapted TRM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFNγ production, equip liver CD8 TRM to survive while exerting local noncytolytic hepatic immunosurveillance.

B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21^–CD27^– atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1^hiatMBC and impairing B cell immunity.

In order to optimally refine the multiple emerging drug targets for hepatitis B virus (HBV), it is vital to evaluate virological and immunological changes at the site of infection. Traditionally liver biopsy has been the mainstay of HBV disease assessment, but with the emergence of non-invasive markers of liver fibrosis, there has been a move away from tissue sampling. Here we argue that liver biopsy remains an important tool, not only for the clinical assessment of HBV but also for research progress and evaluation of novel agents. The importance of liver sampling has been underscored by recent findings of specialised subsets of tissue-resident immune subsets capable of efficient pathogen surveillance, compartmentalised in the liver and not sampled in the blood. Importantly, the assessment of virological parameters, such as cccDNA quantitation, also requires access to liver tissue. We discuss strategies to maximise information obtained from the site of infection and disease pathology. Fine needle aspirates of the liver may allow longitudinal sampling of the local virus/host landscape. The careful utilisation of liver tissue and aspirates in conjunction with blood will provide critical information in the assessment of new therapeutics for the functional cure of HBV.

Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.

Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation, including NK cell responses. Persistent HIV-1 infection leads to a state of chronic immune activation, NK cell subset redistribution, and progressive NK cell dysregulation. In this study, we examined the metabolic processes that characterize NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in HIV-1 ^– individuals infected with human cytomegalovirus (HCMV). However, the bioenergetic advantage of adaptive CD57 ⁺ NKG2C ⁺ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS). Defective OXPHOS was accompanied by increased mitochondrial depolarization, structural alterations, and increased DRP-1 levels promoting fission, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for the NK cell response to receptor stimulation was alleviated upon IL-15 pretreatment, which enhanced mammalian target of rapamycin complex 1 (mTORC1) activity. IL-15 priming enhanced NK cell functionality to anti-CD16 stimulation in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.

Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program. Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance. From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response. Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse. Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.