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Elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases, including Down syndrome (DS), which is the most common chromosomal condition causing intellectual disability globally. Previous research by our group has revealed that treatment with lamivudine, a reverse transcriptase inhibitor, improved neurobehavioral phenotypes and completely rescued hippocampal-dependent recognition memory in a DS mouse model, Ts65Dn. We hypothesized that retrotransposition rates would increase in the Ts65Dn mouse model, and lamivudine could block retrotransposons. We analyzed the differentially expressed long interspersed element-1 (LINE-1 or L1) mapping on MMU16 and 17, and showed for the first time that retrotransposition could be associated with Ts65Dn’s pathology, as misregulation of L1 was found in brain tissues associated with trisomy. In the cerebral cortex, 6 out of 26 upregulated L1s in trisomic treated mice were located in the telomeric region of MMU16 near Ttc3, Kcnj6, and Dscam genes. In the hippocampus, one upregulated L1 element in trisomic treated mice was located near the Fgd4 gene on MMU16. Moreover, two downregulated L1s rescued after treatment with lamivudine were located in the intronic region of Nrxn1 (MMU17) and Snhg14 (MMU7), implicated in a variety of neurodegenerative disorders. To gain further insight into the mechanism of this improvement, we here analyzed the gene expression profile in the hippocampus and cerebral cortex of trisomic mice treated and no-treated with lamivudine compared to their wild-type littermates. We found that treatment with lamivudine rescued the expression of 24% of trisomic genes in the cortex (located on mouse chromosome (MMU) 16 and 17) and 15% in the hippocampus (located in the human chromosome 21 orthologous regions), with important DS candidate genes such as App and Ets2, rescued in both regions.

IntroductionSecond-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients.MethodsReal-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated.ResultsVirological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir

BackgroundSome HIV-1 infected patients are unable to completely recover normal CD4+ T-cell (CD4+) counts after achieving HIV-1 suppression with combined Antiretroviral Therapy (cART), hence being classified as immuno-discordant. The human microbiome plays a crucial role in maintaining immune homeostasis and is a potential target towards immune reconstitution.SettingRECOVER (NCT03542786) was a double-blind placebo-controlled clinical trial designed to evaluate if the novel probiotic i3.1 (AB-Biotics, Sant Cugat del Vallès, Spain) was able to improve immune reconstitution in HIV-1 infected immuno-discordant patients with stable cART and CD4+ counts

Glycosylation of host and viral proteins is an important posttranslational modification needed to ensure correct function of glycoproteins. For this reason, we asked whether inhibition of O-glycosylation during human immunodeficiency virus (HIV) in vitro replication could affect HIV infectivity and replication rates. We used benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (BAGN), a compound that has been widely used to inhibit O-glycosylation in several cell lines. Pretreatment and culture of PHA-blast target cells with BAGN increased the percentage of HIV-infected cells (7.6-fold, p = 0.0115), the per-cell amount of HIV p24 protein (1.3-fold, p = 0.2475), and the viral particles in culture supernatants (7.1-fold, p = 0.0029) compared to BAGN-free cultures. Initiating infection with virus previously grown in the presence of BAGN further increased percentage of infected cells (30-fold, p