The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)(+) interleukin-2 (IL-2)(-) CD8(+) T cells (r = -0.6, P = 0.004). Within this functional CD8(+)IFN-γ(+)IL-2(-) population, cells with the CD45RA(+) chemokine (C-C) receptor 7 (CCR7)(-) phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8(+) T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development.

Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type-1 (HIV-1), these include widely expressed restriction factors1 such as APOBEC3 proteins2, TRIM5α3, tetherin/BST24,5 and SAMHD16,7, as well as additional factors that are stimulated by type-1 interferon (IFN)8,9,10,11,12,13,14. Here, we employ both ectopic expression and gene silencing experiments to define the human dynamin-like, IFN-induced guanosine triphosphatase (GTPase), myxovirus resistance 2 (MX2 or MxB) protein, as a potent inhibitor of HIV-1 infection and as a major effector of IFNα-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has similar to modest effects on divergent simian immunodeficiency viruses (SIVs), and does not inhibit other retroviruses such as murine leukaemia virus (MLV). The capsid (CA) region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step with the nuclear accumulation and chromosomal integration of nascent viral cDNA both being suppressed. Finally, human MX1 (or MxA), a closely related protein that has long been recognised as a broadly acting inhibitor of RNA/DNA viruses, including the orthomyxovirus influenza A virus15,16, does not affect HIV-1,whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilisation may represent a new therapeutic approach for the treatment of HIV/AIDS.

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Summary Background Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.