The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

Influenza virus infection results in altered responses of human mononuclear leukocytes to mitogen and antigen stimulation. We have previously shown (1,2) that depression of such proliferative responses to alternate (nonviral) stimuli was due to decreased monocyte-macrophage accessory cell function, with lymphocyte responsiveness preserved. It has been unclear whether altered influenza virusinfected macrophage accessory cell function was due to (a) inadequate presentation of mitogens, for example, together with class II HLA determinants; (b) inadequate production of essential cofactors, notably IL-1; (c) production of inhibitory factors, such as IL-1 inhibitors; (d) direct cell-cell inhibition; or (e) a combination of such processes. The studies reported herein were undertaken to determine whether the macrophages produce Ik-I or IL-I inhibitors after exposure to the virus.In addition, production of IL-1 and IL-1 inhibitors by respiratory syncytial virus (RSV)l-exposed human macrophages was examined. In contrast to influenza virus, infections with RSV commonly recur, despite serological evidence of immunity of the individual and the lack of clear evidence of antigenic shift or drift of the virus (2-4). RSV infection of human mononuclear leukocytes also results in depressed proliferative responses (2), but RSV differs significantly in ability to induce production of macrophage-derived immunoregulatory factors, such as IFN (2, 5). Materials and MethodsCell Collection and Separation. Mononuclear leukocytes were obtained from the peripheral blood of healthy adult donors by Ficoll-Hypaque sedimentation, and purified monocyte-derived macrophages were obtained by 24-h adherence separation of the cells in plastic culture dishes, as described previously (1, 2). Such macrophage preparations consist of 93-97% monocytes-macrophages by strict criteria for differentiation (1, 6). Unless noted otherwise, macrophages were cultured at 37°C in Eagle's MEM supplemented with 4% FCS, Hepes buffer, and penicillin (100 U/ml).

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the successful use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. His unusual clinical course identifies a key role for SARS-CoV-2 antibodies in both viral clearance and progression to severe disease. In the absence of these confounders, we took an experimental medicine approach to examine the in vivoutility of remdesivir. Over two independent courses of treatment, we observed a dramatic, temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide unambiguous evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

Tissue homeostasis is maintained by the behaviours of lymphocyte clones responding to antigenic triggers in the face of pathogen, environmental, and developmental challenges. Current methodologies for tracking the behaviour of specific lymphocytes identify clones of a defined antigen-receptor - antigen binding affinity. However, lymphocytes can receive antigenic signals from undefined or endogenous antigens, and the strength of each signal, even for the same lymphocyte, varies with accessory signalling, across tissues and across time. We present a novel fate-mapping mouse, that, by tracking lymphocyte clones and their progenies from induced antigen signals, overcomes these hurdles and provides novel insights into the maintenance of tissue homeostasis. We demonstrate the systems use by investigating the maintenance of localised T cell tolerance in tumour immunity. In a murine tumour model, our system reveals how Tregs differentiate to a reversible, tolerance inducing state within the tumour, and recirculate, while CD8+ T cells failing to recirculate, differentiate to an increasingly exhausted, tolerant state in the tumour. These contrasting T cell behaviours provide means by which immunity can tolerate a particular anatomical niche while maintaining systemic clonal protection. Our system can thus explore lymphocyte behaviours that cannot be tracked by previous methods and will therefore provide novel insights into the fundamental mechanisms underlying immunity's role in tissue homeostasis.