Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis

The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention

Lipid profile is associated with treatment regimen in a large cohort of children and adolescents with Type 1 diabetes mellitus: a study from the international SWEET database

Aims: To examine the effect of pump vs injection therapy on the lipid profile of children with Type 1 diabetes mellitus. Methods: A cross-sectional analysis of the lipid profile of children aged ≤ 18 years with Type 1 diabetes mellitus from SWEET, an international diabetes registry, was conducted with a focus on the effect of treatment regimen. Dyslipidaemia was defined as LDL cholesterol ≥2.6 mmol/l or non-HDL cholesterol ≥3.1 mmol/l. LDL and non-HDL cholesterol values among 14 290 children (52% boys, 51% receiving pump therapy) from 60 SWEET centres were analysed by linear and logistic regression analysis adjusted for sex, age, diabetes duration, HbA1c and BMI-standard deviation score group, region, and common interactions between age, sex, HbA1c and BMI. Results: This study confirmed the established associations of increased lipids with female sex, age, diabetes duration, HbA1c and BMI. LDL and non-HDL cholesterol levels were lower in the pump therapy group compared to the injection therapy group [LDL cholesterol: injection therapy 2.44 mmol/l (95% CI 2.42 to 2.46) vs pump therapy 2.39 mmol/l (95% CI 2.37–2.41), P<0.001; non-HDL cholesterol: injection therapy 2.88 mmol/l (95% CI 2.86 to 2.90) vs pump therapy 2.80 mmol/l (95% CI 2.78–2.82), both P<0.0001]. Similarly, the odds ratios for LDL cholesterol ≥2.6 mmol/l [0.89 (95% CI 0.82–0.97)] and non-HDL cholesterol ≥3.1 mmol/l [0.85 (0.78 to 0.93)] were significantly lower in the pump therapy group, even after all adjustments. Conclusions: Our results indicate that pump therapy is associated with a better lipid profile. © 2019 Diabetes U