Integration of SARS-CoV-2 RNA in infected human cells by retrotransposons: an unlikely hypothesis and old viral relationships

Zhang et al. (Proc Natl Acad Sci 118:e2105968118, 2021) recently reported that SARS-CoV-2 RNA can be retrotranscribed and integrated into the DNA of human cells by the L1 retrotransposon machinery. This phenomenon could cause persistence of viral sequences in patients and may explain the prolonged PCR-positivity of SARS-CoV-2 infected patients, even long after the phase of active virus replication has ended. This commentary does critically review the available data on this topic and discusses them in the context of findings made for other exogenous viruses and ancestral endogenous retroviral elements

Prolonged activity of HERV-K(HML2) in Old World Monkeys accounts for recent integrations and novel recombinant variants

Around 8% of the human genome comprises Human Endogenous Retroviruses (HERVs) acquired over primate evolution. Some are specific to primates such as HERV-K, consisting of 10 HML subtypes and including the most recently acquired elements. Particularly, HML2 is the youngest clade, having some human-specific integrations, and while it has been widely described in humans its presence and distribution in non-human primates remain poorly characterized. To investigate HML2 distribution in non-human primates, the present study focused on the characterization of HML2 integrations in Macaca fascicularis and Macaca mulatta which are the most evolutionarily distant species related to humans in the Catarrhini parvorder. We identified overall 208 HML2 proviruses for M. fascicularis (77) and M. mulatta (131). Among them, 46 proviruses are shared by the two species while the others are species specific. Only 12 proviruses were shared with humans, confirming that the major wave of HML2 diffusion in humans occurred after macaques’ divergence. Phylogenetic analysis confirmed structural variations between HML2 macaques’ species-specific proviruses, and the ones shared between macaques and humans. The HML2 loci were characterized in terms of structure, focusing on potential residual open reading frames (ORFs) for gag, pol, and env genes for the latter being reported to be expressed in human pathological conditions. The analysis identified highly conserved gag and pol genes, while the env genes had a very divergent nature. Of the 208 HML2 proviral sequences present in Macaca species, 81 sequences form a cluster having a MER11A, a characteristic HML8 LTR sequence, insertion in the env region indicating a recombination event that occurred between the HML2 env gene and the HML8 LTR. This recombination event, which was shown to be present only in a subset of macaques’ shared sequences and species-specific sequences, highlights a recent viral activity leading to the emergence of an env variant specific to the Old World Monkeys (OWMs). We performed an exhaustive analysis of HML2 in two species of OWMs, in terms of its evolutionary history, structural features, and potential residual coding capacity highlighting recent activity of HML2 in macaques that occurred after its split from the Catarrhini parvorder, leading to the emergence of viral variants, hence providing a better understanding of the endogenization and diffusion of HML2 along primate evolution

Retrotransposons as drivers of Mammalian brain evolution

Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocor-tex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function

HERV‐K(HML7) integrations in the human genome: Comprehensive characterization and comparative analysis in non‐human primates

Endogenous Retroviruses (ERVs) are ancient relics of infections that affected the primate germ line and constitute about 8% of our genome. Growing evidence indicates that ERVs had a major role in vertebrate evolution, being occasionally domesticated by the host physiology. In ad-dition, human ERV (HERV) expression is highly investigated for a possible pathological role, even if no clear associations have been reported yet. In fact, on the one side, the study of HERV expression in high‐throughput data is a powerful and promising tool to assess their actual dysregulation in diseased conditions; but, on the other side, the poor knowledge about the various HERV group genomic diversity and individual members somehow prevented the association between specific HERV loci and a given molecular mechanism of pathogenesis. The present study is focused on the HERV‐K(HML7) group that—differently from the other HERV‐K members—still remains poorly characterized. Starting from an initial identification performed with the software RetroTector, we collected 23 HML7 proviral insertions and about 160 HML7 solitary LTRs that were analyzed in terms of genomic distribution, revealing a significant enrichment in chromosome X and the frequent localization within human gene introns as well as in pericentromeric and centromeric regions. Phy-logenetic analyses showed that HML7 members form a monophyletic group, which based on age estimation and comparative localization in non‐human primates had its major diffusion between 20 and 30 million years ago. Structural characterization revealed that besides 3 complete HML7 pro-viruses, the other group members shared a highly defective structure that, however, still presents recognizable functional domains, making it worth further investigation in the human population to assess the presence of residual coding potential

NLO QCD corrections to the production of Higgs plus two jets at the LHC

We present the calculation of the NLO QCD corrections to the associated production of a Higgs boson and two jets, in the infinite top-mass limit. We discuss the technical details of the computation and we show the numerical impact of the radiative corrections on several observables at the LHC. The results are obtained by using a fully automated framework for fixed order NLO QCD calculations based on the interplay of the packages GoSam and Sherpa. The evaluation of the virtual corrections constitutes an application of the d-dimensional integrand-level reduction to theories with higher dimensional operators. We also present first results for the one-loop matrix elements of the partonic processes with a quark-pair in the final state, which enter the hadronic production of a Higgs boson together with three jets in the infinite top-mass approximation.Comment: 9 pages, 7 figures, references added, published in Phys.Lett.

Automated one-loop calculations with GoSam 2.0

We present the version 2.0 of the program GoSam, which is a public program package to compute one-loop corrections to multi-particle processes. The extended version of the "Binoth-Les-Houches-Accord" interface to Monte Carlo programs is also implemented. This allows a large flexibility regarding the combination of the code with various Monte Carlo programs to produce fully differential NLO results, including the possibility of parton showering and hadronisation. We describe the new features of the code and illustrate the wide range of applicability for multi-particle processes at NLO, both within and beyond the Standard Model.Comment: 9 pages, talk given at the conference "Loops and Legs in Quantum Field Theory", Weimar, Germany, April 201

Contribution of human retroviruses to disease development-A focus on the HIV- And HERV-cancer relationships and treatment strategies

Animal retroviruses are known for their transforming potential, and this is also true for the ones hosted by humans, which have gathered expanding attention as one of the potent causative agents in various disease, including specific cancer types. For instance, Human T Lymphotropic virus (HTLV) is a well-studied class of oncoviruses causing T cell leukemia, while human immunodeficiency virus (HIV) leads to acquired immunodeficiency syndrome (AIDS), which is linked to a series of defining cancers including Kaposi sarcoma, certain types of non-Hodgkin lymphoma, and cervical cancer. Of note, in addition to these “modern” exogenous retroviruses, our genome harbors a staggering number of human endogenous retroviruses (HERVs). HERVs are the genetic remnants of ancient retroviral germline infection of human ancestors and are typically silenced in normal tissues due to inactivating mutations and sequence loss. While some HERV elements have been appropriated and contribute to human physiological functions, others can be reactivated through epigenetic dysregulations to express retroviral elements and promote carcinogenesis. Conversely, HERV replication intermediates or protein products can also serve as intrinsic pathogen-associated molecular patterns that cause the immune system to interpret it as an exogenous infection, thereby stimulating immune responses against tumors. As such, HERVs have also been targeted as a potential internal strategy to sensitize tumor cells for promising immunotherapies. In this review, we discuss the dynamic role of human retroviruses in cancer development, focusing on HIV and HERVs contribution. We also describe potential treatment strategies, including immunotherapeutic targeting of HERVs, inhibiting DNA methylation to expose HERV signatures, and the use of antiretroviral drugs against HIV and HERVs, which can be employed as prospective anti-cancer modalities

Vestibular rehabilitation training in patients with subacute stroke: a preliminary randomized controlled trial

Background: Vestibular rehabilitation (VR) consists in a customized exercise program patient-centred that includes a combination of different exercise components with the aim to promote gaze stability, improve balance and gait, and facilitate somatosensory integration. OBJECTIVE: The aim of this study was to investigate the effect of customized vestibular rehabilitation training on gait stability of patients with subacute stroke. METHODS: Twenty-five inpatients (12 M, age: 64.1±12.1 years) with diagnosis of subacute stroke were enrolled and randomized in two groups. All patients were evaluated before and after 4 weeks of training sessions. An instrumented 10-Meter Walk Test together with traditional clinical scales were used to assess VR effects. To investigate if any fall event occurred after patients' dismissal, they were followed-up at three and twelve months after dismissal. RESULTS: Higher values of walking speed and stride length were observed in the VR group. Conversely, no significant difference was found in terms of trunk stability. The results of between-group comparison highlight significant differences between the two groups for different clinical scale scores. CONCLUSION: VR could be included into a rehabilitation program for patients with stroke for improving their gait and dynamic balance acting on their vestibular system as facilitator of recovery

GoSam-2.0: a tool for automated one-loop calculations within the Standard Model and beyond

We present the version 2.0 of the program package GoSam for the automated calculation of one-loop amplitudes. GoSam is devised to compute one-loop QCD and/or electroweak corrections to multi-particle processes within and beyond the Standard Model. The new code contains improvements in the generation and in the reduction of the amplitudes, performs better in computing time and numerical accuracy, and has an extended range of applicability. The extended version of the "Binoth-Les-Houches-Accord" interface to Monte Carlo programs is also implemented. We give a detailed description of installation and usage of the code, and illustrate the new features in dedicated examples.Comment: replaced by published version and reference adde

Identification and characterization of ERV-W-like sequences in Platyrrhini species provides new insights into the evolutionary history of ERV-W in primates

Background: Endogenous Retroviruses (ERVs) constitute approximately 8% of every human genome and are relics of ancestral infections that affected the germ line cells. The ERV-W group contributed to primate physiology by providing an envelope protein (Syncytin-1) that has been adopted for placenta development in hominoids. Expression of Human ERV-W (HERV-W) sequences is investigated for a pathological role in various human diseases. Results: We previously characterized ERV-W group genomic sequences in human and non-human Catarrhini species. We now investigated ERV-W-like sequences in the parvorder Platyrrhini, especially regarding two species with complete genome assemblies, namely marmoset (Callithrix jacchus) and squirrel monkey (Saimiri boliviensis). We identified in both species proviral sequences, annotated as ERV1-1 in respective genome assemblies, sharing high sequence similarities with Catarrhini ERV-W. A total of 130 relatively intact proviruses from the genomes of marmoset and squirrel monkey were characterized regarding their structural and evolutionarily relationships with Catarrhini ERV-W elements. Platyrrhini ERV-W sequences share several structural features with Catarrhini ERV-W elements and are closely related phylogenetically with the latter as well as with other ERV-W-related gammaretrovirus-like ERVs. The ERV-W group colonized Platyrrhini primates of both Callitrichidae and Atelidae lineages, with provirus formations having occurred mostly between 25 and 15 mya. Two LTR subgroups were associated with monophyletic proviral bodies. A pre-gag region appears to be a sequence feature common to the ERV-W group: it harbors a putative intron sequence that is missing in some ERV-W loci, holding a putative ORF as well. The presence of a long pre-gag portion was confirmed among all gammaretroviral ERV analyzed, suggesting a role in the latter biology. It is noteworthy that, contrary to Catarrhini ERV-W, there was no evidence of L1-mediated mobilization for Platyrrhini ERV-W sequences. Conclusions: Our data establish that ERV-W is not exclusive to Catarrhini primates but colonized both parvorders of Simiiformes, providing further insight into the evolution of ERV-W and the colonization of primate genomes