We previously demonstrated that NK cells from HIV-infected individuals have elevated expression of activation markers, spontaneously degranulate ex vivo, and decrease expression of a signal-transducing protein for NK-activating receptors, FcRγ. Importantly, these changes were maintained in virologically suppressed (VS) individuals receiving combination antiretroviral therapy (cART). In this study, we show that loss of FcRγ is caused by the expansion of a novel subset of FcRγ−CD56dim NK cells with an altered activation receptor repertoire and biological properties. In a cross-sectional study, FcRγ− NK cells as a proportion of total CD56dim NK cells increased in cART-naive viremic HIV-infected individuals (median [interquartile range] = 25.9 [12.6–56.1] compared with 3.80 [1.15–11.5] for HIV− controls, p < 0.0001) and in VS HIV-infected individuals (22.7 [13.1–56.2] compared with 3.80 [1.15–11.5], p = 0.0004), with no difference between cART-naive and VS patients (p = 0.93). FcRγ− NK cells expressed no NKp30 or NKp46. They showed greater Ab-dependent cellular cytotoxicity activity against rituximab-opsonized Raji cells and in a whole-blood assay measuring NK responses to overlapping HIV peptides, despite having reduced CD16 expression compared with conventional NK cells. Their prevalence correlated with CMV Ab titers in HIV− subjects but not in HIV+ individuals, and with the inflammatory marker CXCL10 in both groups. The expansion of a subset of NK cells that lacks NKp30 and NKp46 to ∼90% of CD56dim NK cells in some VS HIV+ individuals may influence NK-mediated immunosurveillance in patients receiving cART.

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Cytomegalovirus (CMV) establishes lifelong infections with episodes of active replication. We hypothesized that recurrent CMV replication in older individuals may suppress protective immune responses to non-tuberculous mycobacteria (NTM) and so potentiate pulmonary disease. Accordingly, levels of antibodies to three CMV antigen preparations were higher in NTM patients than in age-matched controls. This did not reflect broad-spectrum B cell activation as total immunoglobulin levels were not equivalently increased.

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Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.