B1 cells are evolutionarily conserved innate-like cells that share many features with macrophages. It has also been established that B1 cells have a close developmental relationship with macrophages. However, whether B1 cells are able to act as professional phagocytic cells is not clear. In this study, we report that mouse peritoneal cavity (PerC) B cells demonstrate in vivo and in vitro phagocytic activities for Staphylococcus aureus, Escherichia coli, and polystyrene fluorescent microspheres. Approximately 5% of PerC B cells, mainly B1b cells, showed phagocytic activity. Ingested microbes were killed efficiently in the phagolysosome. The antigen-specific B-cell antigen receptor promoted B-cell phagocytosis, resulting in antigen presentation to T cells after uptake of bacteria. Our results reveal for the first time that mouse B1 cells have active phagocytic capabilities and thereby act as a bridge linking innate and adaptive immunity.

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread®) and tenofovir alafenamide (Vemlidy®) against HIV and HBV infections and adefovir dipivoxil (Hepsera®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex®) against HSV-1 and VZV infections and stavudine (Zerit®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex®, Zelitrex®) against HSV and VZV and rabacfosadine (Tanovea®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.

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HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3’-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography that identifies two leads that bind the P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized, two of which show noticeable RT inhibition. An engineered RT/DNA aptamer complex could trap the transient P-pocket in solution, and structures of the RT/DNA complex were determined in the presence of an inhibitory fragment. A synthesized analog bound at P-pocket is further analyzed by single-particle cryo-EM. Identification of the P-pocket within HIV RT and the developed structure-based platform provide an opportunity for the design new types of polymerase inhibitors.

HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3’-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography and identified binding of two to P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized of which two showed noticeable RT inhibition. An engineered RT/DNA aptamer complex trapped the transient P-pocket in solution. Structures of the RT/DNA complex were determined with a fragment and a synthesized analog bound at P-pocket by single-particle cryo-EM. Identification of P-pocket and the devised structure-based platform provide an opportunity for designing new types of polymerase inhibitors.