Summary Paragraph All known recently emerged human coronaviruses likely originated in bats 1 . Here, we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbor endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained Type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for coronavirus infection. Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II-III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.

Author contributions T.D. and S.S. designed the experiments, supervised the project, and wrote the manuscript. X.H. performed the adaptive and innate immunobiology experiments, molecular biology and imaging studies and cell culture work and analyzed the data. A.G. performed imaging studies and analyzed the data. D.W. performed the in vivo and immunofluorescence imaging studies (confocal microscopy) and histopathology. G.T. performed imaging studies and cell injections. C.D. and W.O.T. generated BLT mice and performed the BLT imaging experiments. A.W. and J.V.G. designed and supervised the experiments using BLT mice. W.O.T. and C.D. performed the experiments using BLT mice. H.R., M.M.D. and L.L.L. gave technical support and conceptual advice. All authors contributed to editing the manuscript.

Summary Paragraph Long-lasting, latently-infected, resting CD4 + T cells are the greatest obstacle to cure HIV infection, as they persist despite decades of treatment with ART. Estimates indicate the need for >70 years of continuous, fully suppressive, antiretroviral therapy (ART) to eliminate the HIV reservoir 1 . Alternatively, induction of HIV from its latent state could accelerate decline of the reservoir, thereby shortening time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in peripheral blood with minimal focus on tissue reservoirs and had limited effect 2 - 9 . Here we show that activation of the non-canonical NF-κB signaling pathway via AZD5582 results in induction of HIV- and SIV-RNA expression in the blood and tissues of ART-suppressed bone marrow/liver/thymus (BLT) humanized mice and rhesus macaques. Analysis of resting CD4 + T cells from tissues after AZD5582 treatment revealed increased SIV-RNA in lymph nodes in macaques and robust induction of HIV in virtually all tissues analyzed in humanized mice including lymph nodes, thymus, bone marrow, liver, and lung. This promising new approach to latency reversal, in combination with appropriate tools for systemic clearance of persistent HIV infection, greatly increases opportunities for HIV eradication.

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Abstract. During heavy seasonal rainfall in 1996, concurrent epidemics of dengue and leptospirosis occurred in an urban center in northeastern Brazil. We interviewed 110 cases of leptospirosis hospitalized a median of seven days after the onset of illness to evaluate the impact of the dengue epidemic on the triage of suspected leptospirosis from ambulatory clinics to the infectious disease reference hospital. Within the first three days of illness, 46 (42%) cases sought their first medical evaluation, and 28 (61% of 46) received a diagnosis of dengue. Dengue diagnoses were associated with a median of five days delay in referral to the infectious disease hospital. Patients who reported initial diagnoses of dengue were more likely than other patients to have required admission to the intensive care unit (odds ratio [OR] ϭ 2.7, 95% confidence interval [CI] ϭ 0.8-9.5) and to have died during hospitalization (OR ϭ 5.1, 95% CI ϭ 0.8-55.0). These findings indicate that diagnostic confusion between the early symptoms of leptospirosis and dengue may have contributed to the high mortality observed during the leptospirosis epidemic.