Antiretroviral drugs have also been

Antiretroviral drugs have also been a focus of attention for this purpose. A differential impact of drug PR171 and individual drugs has been the hypothesis for some analysis of randomized clinical trials. Information on the impact of different ART regimens on inflammatory biomarkers linked with mortality remains, however, very limited. Recently, integrase inhibitors have shown to improve inflammation or immune activation markers when compared to non-nucleoside reverse transcriptase inhibitors. In particular, when compared to efavirenz, raltegravir normalized the CD4/CD8 ratio faster than efavirenz (), and elvitegravir/cobicistat induced larger decreases of markers of monocyte activation (sCD14), systemic (hsCRP) and vascular inflammation (Lp-PLA2) (). No such analysis has been performed so far with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) which are included in all the recommended regimens for treatment initiation of HIV-infection. For this reason, the article by Funderburg et al. in this issue of () is especially pertinent. Based on a large, double-blind clinical trial, this substudy examines changes in different biomarkers of local and systemic inflammation, comparing tenofovir alafenamide (TAF) with tenofovir disoproxil fumarate (TDF) both in combination with emtricitabine and elvitegravir/cobicistat. TAF is a new prodrug of tenofovir diphosphate that has been shown to have an efficacy similar to TDF while improving the renal and bone toxicity in clinical trials. However, information on the changes in markers of inflammation is lacking. The results show that, as expected, there were significant declines of most markers from baseline in both arms, and that TAF is as effective as TDF at reducing markers of immune activation and inflammation associated with the development of non-AIDS events and all-cause mortality.
Infections with parasitic helminths of the genus are considered one of the most socioeconomically devastating parasitic diseases, with hundreds of millions of people infected worldwide. These infections can result in significant morbidity primarily due to parasite-derived eggs that accumulate in tissues, such as the liver (in the case of and infection), where they drive inflammation, tissue damage and fibrosis (). Macrophages have been shown to play a key modulatory role in this egg-induced immunopathology. Before the onset of egg-laying by the adult worms, the host immune response is characterized by a T helper 1 (Th1) response, which through the secretion of IFN-γ promotes the differentiation of macrophages towards a more pro-inflammatory classically activated phenotype (‘M1’). Upon egg deposition a potent type 2 immune response is triggered, in which Th2 cells and Type 2 cytokine-driven alternatively activated macrophages (‘M2’) predominate. This M2 phenotype of macrophages is crucial for the host to survive acute schistosomiasis, by keeping Type 1 inflammatory responses, including those mediated by M1 macrophages, in check that would otherwise result in potentially lethal tissue-damage. Moreover, M2 macrophages are involved in granuloma formation and induction of fibrosis around eggs trapped in tissues, which is thought to be an important host protective mechanism against egg-driven pathology (). This illustrates the importance of a tight regulation of macrophage polarization during schistosomiasis and disease outcome. However, the molecular mechanisms that control macrophage polarization in egg-affected tissues are still not fully understood. In the current issue He and coworkers provide for the first time support for an important role for a specific microRNA (miRNA), miRNA-146, in regulating the balance between M2 and M1 macrophage polarization during -induced hepatic schistosomiasis (). miRNAs are small ubiquitously expressed non-coding RNAs, that regulate gene expression at the post-transcriptional level through RNA silencing and thereby play important roles in various aspects of cell biology, including regulation of the functional properties of immune cells (). While the role for miRNAs in schistosome biology and development has become an intense area of research (), the role of host miRNAs in shaping immune responses against these parasites has been poorly characterized. In a previous study He and coworkers performed a miRNA microarray on livers from infected mice and identified miRNA-146 as one of several strongly upregulated miRNAs in response to infection (). This prompted them to study this miRNA species in more detail in the current study. They found two miRNA-146 family members, miRNA-146a and b, to be highly induced in liver resident macrophages, the Kupffer cells, from around day 42 after infection, which coincides with the start of egg deposition in the liver. Using complementary and approaches, they went on to show that the promotor region of the gene sequence encoding miRNA-146b contains response elements for transcription factors STAT3 and -6 and that as result Th2-associated cytokines IL-10, IL-4 and IL-13 could promote expression of this miRNA in macrophages. Importantly, He and coworkers identified STAT1, a critical component of IFN-γ signaling, as a direct target of miRNA-146a/b and as a result found IFN-γ-induced expression of M1 markers could be suppressed by these miRNAs.