Unique functions of repetitive transcriptomes

Repetitive sequences occupy a huge fraction of essentially every eukaryotic genome. Repetitive sequences cover more than 50% of mammalian genomic DNAs, whereas gene exons and protein-coding sequences occupy only ~3% and 1%, respectively. Numerous genomic repeats include genes themselves. They generally encode "selfish" proteins necessary for the proliferation of transposable elements (TEs) in the host genome. The major part of evolutionary "older" TEs accumulated mutations over time and fails to encode functional proteins. However, repeats have important functions also on the RNA level. Repetitive transcripts may serve as multifunctional RNAs by participating in the antisense regulation of gene activity and by competing with the host-encoded transcripts for cellular factors. In addition, genomic repeats include regulatory sequences like promoters, enhancers, splice sites, polyadenylation signals, and insulators, which actively reshape cellular transcriptomes. TE expression is tightly controlled by the host cells, and some mechanisms of this regulation were recently decoded. Finally, capacity of TEs to proliferate in the host genome led to the development of multiple biotechnological applications

Model structure of APOBEC3C reveals a binding pocket modulating ribonucleic acid interaction required for encapsidation

Human APOBEC3 (A3) proteins form part of the intrinsic immunity to retroviruses. Carrying 1 or 2 copies of a cytidine deaminase motif, A3s act by deamination of retroviral genomes during reverse transcription. HIV-1 overcomes this inhibition by the Vif protein, which prevents incorporation of A3 into virions. In this study we modeled and probed the structure of APOBEC3C (A3C), a single-domain A3 with strong antilentiviral activity. The 3-dimensional protein model was used to predict the effect of mutations on antiviral activity, which was tested in a Δvif simian immunodeficiency virus (SIV) reporter virus assay. We found that A3C activity requires protein dimerization for antiviral activity against SIV. Furthermore, by using a structure-based algorithm for automated pocket extraction, we detected a putative substrate binding pocket of A3C distal from the zinc-coordinating deaminase motif. Mutations in this region diminished antiviral activity by excluding A3C from virions. We found evidence that the small 5.8S RNA specifically binds to this locus and mediates incorporation of A3C into virus particles

In-depth virological and immunological characterization of HIV-1 cure after CCR5 Delta 32/Delta 32 allogeneic hematopoietic stem cell transplantation

Despite scientific evidence originating from two patients published to date that CCR5 Delta 32/Delta 32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5 Delta 32/Delta 32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5 Delta 32/Delta 32 HSCT. The recipient of an allogeneic stem cell transplant from a CCR5 Delta 32/Delta 32 donor shows evidence of HIV type 1 cure, including the absence of a viral rebound over 4 years after stopping antiretroviral treatment