Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells

Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells’ response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells

Effect of eradication of Helicobacter pylori on expression levels of FHIT, IL-8 and P73 in gastric mucosa of first-degree relatives of gastric cancer patients.

OBJECTIVES:Helicobacter pylori (H. pylori) infection plays an important role in the carcinogenesis and development of gastric cancer. Eradication of H. pylori can effectively reduce the risk of gastric cancer, but the underlying mechanisms are not fully understood. This study aimed to investigate the effect of eradication of H. pylori on the expression levels of FHIT, IL-8 and P73 in the gastric mucosa of first-degree relatives of gastric cancer patients. METHODS:One hundred and thirty-two patients with functional dyspepsia having first-degree relatives with gastric cancer were prospectively recruited in this study. Nine patients presented with H. pylori infection and family histories of gastric cancer, 61 with H. pylori infection and without family histories of gastric cancer, 6 without H. pylori infection and with family histories of gastric cancer, and 56 without H. pylori infection and family histories of gastric cancer. The protein and mRNA expression levels of FHIT, IL-8 and P73 in gastric mucosa of the subjects were detected by immunohistochemical staining and polymerase chain reaction, respectively. RESULTS:Compared with the patients without H. pylori infection and family histories of gastric cancer, both the protein and mRNA levels of FIHT significantly decreased in patients with H. pylori infection and/or family histories of gastric cancer, and both the protein and mRNA levels of IL-8 significantly increased. After eradication of H. pylori, both the protein and mRNA levels of FHIT were significantly higher, and both the protein and mRNA levels of IL-8 were significantly lower. However, H. pylori infection and family histories of gastric cancer had no major effect on P73 expression. CONCLUSIONS:Down-regulation of FHIT and up-regulation of IL-8 may be involved in the pathogenesis of H. pylori infection in the first-degree relatives of gastric cancer patients

Clinical characteristics of patients in this study.

<p>This is the Table 2 legend. Group A: patients with both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer. Group B: patients with <i>H</i>. <i>pylori</i> infection and without family histories of gastric cancer. Group C: patients without <i>H</i>. <i>pylori</i> infection and with family histories of gastric cancer. Group D: patients without both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer.</p><p>Clinical characteristics of patients in this study.</p

Effect of <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer on mRNA expression of FHIT, IL-8 and P73 before eradication of <i>H</i>. <i>pylori</i>.

<p>Group A: patients with both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer. Group B: patients with <i>H</i>. <i>pylori</i> infection and without family histories of gastric cancer. Group C: patients without <i>H</i>. <i>pylori</i> infection and with family histories of gastric cancer. Group D: patients without both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer. Data were expressed as the mean±standard deviation. Statistical differences were determined by Kruskal-Wallis rank test. Compared with Group A, * <i>P</i><0.01; compared with Group B, # <i>P</i><0.05; compared with Group A+B, $; compared with Group A+C, ¶ <i>P</i><0.05.</p

Effect of <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer on protein expression of FHIT, IL-8 and P73 before eradication of <i>H</i>. <i>pylori</i>.

<p>Group A: patients with both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer. Group B: patients with <i>H</i>. <i>pylori</i> infection and without family histories of gastric cancer. Group C: patients without <i>H</i>. <i>pylori</i> infection and with family histories of gastric cancer. Group D: patients without both <i>H</i>. <i>pylori</i> infection and family histories of gastric cancer. Data were expressed as the mean ±standard deviation. Statistical differences were determined by Kruskal-Wallis rank test. Compared with Group A, * <i>P</i><0.01; compared with Group B, # <i>P</i><0.05; compared with Group A+B, $; compared with Group A+C, ¶ <i>P</i><0.05.</p