A formylpeptide receptor, FPRL1, acts as an efficient coreceptor for primary isolates of human immunodeficiency virus

<p>Abstract</p> <p>Background</p> <p>More than 10 members of seven-transmembrane G protein-coupled receptors (GPCRs) have been shown to work as coreceptors for human immunodeficiency virus type 1 (HIV-1), HIV type 2 (HIV-2), and simian immunodeficiency viruses (SIVs). As a common feature of HIV/SIV coreceptors, tyrosine residues are present with asparagines, aspartic acids or glutamic acids in the amino-terminal extracellular regions (NTRs).</p> <p>We noticed that a receptor for N-formylpeptides, FPRL1, also contains two tyrosine residues accompanied by glutamic acids in its NTR. It was reported that monocytes expressing CCR5 and FPRL1 in addition to CD4 are activated by treatment with ligands or agonists of FPRL1. Activated monocytes down-modulate CCR5 and become resistant to infection by HIV-1 strains. Thus, FPRL1 plays important roles in protection of monocyptes against HIV-1 infection. However, its own coreceptor activity has not been elucidated yet. In this study, we examined coreceptor activities of FPRL1 for HIV/SIV strains including primary HIV-1 isolates.</p> <p>Results</p> <p>A CD4-transduced human glioma cell line, NP-2/CD4, is strictly resistant to HIV/SIV infection. We have reported that when NP-2/CD4 cells are transduced with a GPCR having coreceptor activity, the cells become susceptible to HIV/SIV strains. When NP-2/CD4 cells were transduced with FPRL1, the resultant NP-2/CD4/FPRL1 cells became markedly susceptible to some laboratory-adapted HIV/SIV strains. We found that FPRL1 is also efficiently used as a coreceptor by primary HIV-1 isolates as well as CCR5 or CXCR4.</p> <p>Amino acid sequences linked to the FPRL1 use could not be detected in the V3 loop of the HIV-1 Env protein. Coreceptor activities of FPRL1 were partially blocked by the forymyl-Met-Leu-Phe (fMLF) peptide.</p> <p>Conclusion</p> <p>We conclude that FPRL1 is a novel and efficient coreceptor for HIV/SIV strains. FPRL1 works as a bifunctional factor in HIV-1 infection. Namely, the role of FPRL1 in HIV-1 infection is protective and/or promotive in different conditions. FPRL1 has been reported to be abundantly expressed in the lung, spleen, testis, and neutrophils. We detected mRNA expression of FPRL1 in 293T (embryonal kidney cell line), C8166 (T cell line), HOS (osteosarcoma cell line), Molt4#8 (T cell line), U251MG (astrocytoma cell line), U87/CD4 (CD4-transduced glioma cell line), and peripheral blood lymphocytes. Roles of FPRL1 in HIV-1 infection <it>in vivo </it>should be further investigated.</p

Broad Efficacy of a Computationally Designed ACE2 Decoy Against SARS-CoV-2 Omicron Variants and Related Viruses In Vitro and In Vivo

Background: The SARS-CoV-2 omicron variant (B.1.1.529) and its sublineages are currently the dominant variants in the United States accounting for 100% of COVID-19 cases. Problem: The S protein receptor-binding domain (RBD), located in the S1 subunit of the S protein, binds the human angiotensin-converting enzyme 2 (hACE2) leading to S1 shedding and proteolytic processing of S2 that is important for membrane fusion and release of viral RNA. Various neutralizing therapeutics including protein minibinders, peptides, monoclonal antibodies, and nanobodies have been developed to block the critical interaction between the RBD and hACE2. However, these therapeutics are often developed against the S protein of wildtype or a specific variant of SARSCoV- 2, making them highly susceptible to mutational escape.1 Solution: A strategy employed by our group includes using sACE2 (soluble dimeric ACE2 that contains both the protease and dimerization domains) with enhanced S RBD affinity to outcompete native ACE2 expressed on host cells, acting as a ‘decoy’ to block the interaction between the RBD and hACE2 (Figure 1). sACE2 has moderate affinity for the S protein (~20 nM)2. Therefore, sACE2 must be engineered (by introducing affinity enhancing mutations) to bind with tighter affinity to outcompete membrane bound ACE2-S interaction and rival the potency of mAbs. These sACE2 derivatives maintain close similarity to the native ACE2 receptor making them extremely resistant to virus escape. Any mutation in the RBD that limits binding to the sACE2 derivative will likely have reduced binding towards native ACE2 receptors potentially making the virus unfit to propagate.https://jdc.jefferson.edu/aoa_research_symposium_posters/1000/thumbnail.jp

Temporal resolution measurement of 128-slice dual source and 320-row area detector computed tomography scanners in helical acquisition mode using the impulse method

Purpose: To analyse the temporal resolution (TR) of modern computed tomography (CT) scanners using the impulse method, and assess the actual maximum TR at respective helical acquisition modes. Methods: To assess the actual TR of helical acquisition modes of a 128-slice dual source CT (DSCT) scanner and a 320-row area detector CT (ADCT) scanner, we assessed the TRs of various acquisition combinations of a pitch factor (P) and gantry rotation time (R). Results: The TR of the helical acquisition modes for the 128-slice DSCT scanner continuously improved with a shorter gantry rotation time and greater pitch factor. However, for the 320-row ADCT scanner, the TR with a pitch factor of 1.0, it was approximately one half of the gantry rotation time. The maximum TR values of single- and dual-source helical acquisition modes for the 128-slice DSCT scanner were 0.138 (R/. P = 0.285/1.5) and 0.074. s (R/. P = 0.285/3.2), and the maximum TR values of the 64. ×. 0.5- and 160. ×. 0.5-mm detector configurations of the helical acquisition modes for the 320-row ADCT scanner were 0.120 (R/. P = 0.275/1.375) and 0.195. s (R/. P = 0.3/0.6), respectively. Conclusion: Because the TR of a CT scanner is not accurately depicted in the specifications of the individual scanner, appropriate acquisition conditions should be determined based on the actual TR measurement. © 2016 Associazione Italiana di Fisica Medica