Charles R. Crain

Summary: Chronic hepatitis B is characterized by a decades-long evolving engagement between host immunity and the hepatitis B virus (HBV). Understanding the molecular characteristics of HBV-specific CD8 T cells linked to control of viral replication and antigenemia is essential to design effective immunotherapeutic modalities. Here we show that HBV-specific CD8 T cells, even during infection stages with extremely high viral loads, lack the features of terminally exhausted CD8 T cells observed in chronic HCV and HIV infection or cancer. Instead, we observe emerging gene expression programs over disease stages that correlate with increasing HBV control, which include a bona fide cytotoxic and T-cell localization program associated with low levels of viral replication, and a second NK-like T-cell program that combines expression of classical NK markers ( KIR s, KLR s, FCGR3A , TYROBP , IKZF2 ) with cytotoxic genes ( GZMB , GNLY , PRF1 ), which emerges with complete control of HBV viremia and antigenemia. We also found enrichment of both CD8 T-cell programs in HIV-specific CD8 T cells from HIV elite controllers, supporting a conserved role in controlling persistent viral infections with viral reservoirs.

Individuals who durably control HIV after cessation of antiretroviral therapy (ART) are of great interest for HIV cure efforts, but the correlates of posttreatment control remain incompletely understood. Here, we show across a diverse cohort of posttreatment controllers (PTCs), posttreatment noncontrollers (NCs), and spontaneous elite controllers (ECs) that robust expansion of HIV-specific CD8 ⁺ T cells and reduced viral reservoir diversity were strongly associated with durable (>1 year) viral suppression after ART cessation. In addition, HIV-specific CD8 ⁺ T cells in PTCs exhibited a stemlike memory phenotype, characterized by high TCF-1 (T cell factor 1) and low TOX (thymocyte selection–associated HMG box) expression, and readily differentiated into cytolytic effectors. Mapping of CD8 ⁺ T cell responses from PTCs revealed broad targeting of epitopes in a conserved autologous reservoir, whereas preferential targeting of epitopes derived from mutationally constrained regions was primarily a feature of CD8 ⁺ T cells from ECs. Univariable and additive analyses revealed a link between HIV-specific CD8 ⁺ T cell expansion, a stemlike phenotype, and conservation of human leukocyte antigen class I–restricted viral epitopes with posttreatment control. Together, these findings identify features of HIV-specific CD8 ⁺ T cells and the viral reservoir that are associated with sustained HIV control after ART cessation, informing future immunotherapeutic strategies toward achieving an HIV cure.

To explore the use of human B cell receptor (BCR) knock-in mice for broadening antibody responses, we diversified CR3022, a monoclonal antibody (mAb) originally identified in a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) convalescent patient. This mAb targets a conserved epitope on the coronavirus receptor-binding domain (RBD). We took advantage of high- and low-affinity CR3022 BCR knock-in mice and immunized them with SARS-CoV-2 Wuhan RBD trimers to expand the breadth of these antibodies toward this virus. The resulting antibodies retained the ability to neutralize SARS-CoV and exhibited enhanced affinity and neutralization against the SARS-CoV-2 WA1/2020 strain, as well as the Delta (B.1.617.2) and Omicron KP.3 variants. They also showed broadened reactivity to two bat coronaviruses: WIV1 and, to a lesser potency, BtKY72. Structural analysis revealed key mutations that enhanced binding and neutralization, highlighting the importance of epitope accessibility and variant-specific conformations in antibody diversification. These findings demonstrate that human BCR-expressing mouse models can generate effective antibodies with broad neutralizing activity against viral epitopes.