No abstract

Innate immune responses play a critical role in the control of early virus replication and dissemination. It remains unknown, however, how SARS-CoV evades respiratory innate immunity to establish a systemic infection. Here, we show in Chinese macaques that SARS-CoV traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by T cells, MAC387+ and CD163+ monocytes/macrophages followed by limited viral replication in the lung but persistent viral shedding into the upper airway. Mucosal monocytes/macrophages sequestered virions in intracellular vesicles together with infected Langerhans cells (LCs) and migrated into the tonsils and/or draining lymph nodes (LNs) within 2 days. In lymphoid tissues, viral RNA and proteins were detected in infected monocytes upon differentiation into dendritic cells (DCs) within 3 days. Systemic viral dissemination was observed within 7 days. This study provides a comprehensive overview of the spatiotemporal interactions of SARS-CoV, monocytes/macrophages and the dendritic cell network in mucosal tissues and highlights the fact that while these innate cells contribute to viral clearance, they probably also serve as shelters and vehicles to provide a mechanism for the virus to escape host mucosal innate immunity and disseminate systemically.

Highly active antiretroviral therapy (HAART) has been successful in reducing HIV-1-associated morbidity and mortality since its introduction in 1996. It, however, fails to eradicate HIV-1 infection thoroughly. The high cost of life-long HAART and the emergence of drug resistance among HIV-1-infected individuals have brought renewed pressure for the discovery of novel antivirals and alternative medicines. Traditional Chinese medicine (TCM) is one of the mainstreams of complementary and alternative medicine, and serves as rich resources for new drug development. Despite almost 100 plant-derived compounds are in clinical trials, few target HIV-1 infection. In this study, we discovered that extract of Sanguisorba officinalis (SOE) has anti-HIV-1 activities. Using a cell-based assay and single-cycle luciferase reporter viruses pseudotyped with envelopes from HIV-1 or control viruses, we found that SOE exhibited significant inhibitory ability against both CCR5 and CXCR4 tropic HIV-1 (ADA and HXB2) with respective IC50 values of 1.91±0.16 μg/ml and 3.70±0.53 μg/ml. Interestingly, SOE also inhibited SIV infection but failed to block vesicular stomatitis virus (VSV), SARS-CoV and influeunza H5N1 pseudoviruses. Furthermore, we showed that SOE had no effects on post-entry events of HIV-1 replication. It blocked entry by acting on viral envelope directly because SOE pre-treatment with the virus but not with cell lines expressing viral receptors showed the maximal inhibitory activity. In addition, SOE was able to inhibit reverse-transcription-inhibitor-resistant viruses (K103N, Y188L, and K103N/Y188L/G190A) and a protease-inhibitor-resistant strain (PI-2840). Our findings demonstrated SOE as a novel and specific entry inhibitor, which shed lights on the discovery of anti-HIV-1 drugs from traditional herbal medicines.

Background Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to simian human immunodeficiency virus (SHIV) to investigate whether TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection. Methods Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks. Animals received clinical doses of FTC/TAF (n = 6) or TAF (n = 9) orally 24 hours before and 2 hours after each weekly virus exposure. Infection was compared with 21 untreated controls. Results Five of the 6 animals in the FTC/TAF and 4 of the 9 animals in the TAF alone group were protected against infection (P = .001 and P = .049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% confidence interval [CI], 34.9%–98.8%) and 57.8% (95% CI, −8.7% to 83.6%), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (P = .005 and P = .114). Median tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; P = .921). Conclusions Emtricitabine/TAF provided a level of protection against vaginal challenge similar to FTC/TFV disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women.