Endogenous retroelement expression in the gut microenvironment of people living with HIV-1.

BACKGROUND: Endogenous retroelements (EREs), including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), comprise almost half of the human genome. Our previous studies of the interferome in the gut suggest potential mechanisms regarding how IFNb may drive HIV-1 gut pathogenesis. As ERE activity is suggested to partake in type 1 immune responses and is incredibly sensitive to viral infections, we sought to elucidate underlying interactions between ERE expression and gut dynamics in people living with HIV-1 (PLWH). METHODS: ERE expression profiles from bulk RNA sequencing of colon biopsies and PBMC were compared between a cohort of PLWH not on antiretroviral therapy (ART) and uninfected controls. FINDINGS: 59 EREs were differentially expressed in the colon of PLWH when compared to uninfected controls (padj <0.05 and FC ≤ -1 or ≥ 1) [Wald's Test]. Of these 59, 12 EREs were downregulated in PLWH and 47 were upregulated. Colon expression of the ERE loci LTR19_12p13.31 and L1FLnI_1q23.1s showed significant correlations with certain gut immune cell subset frequencies in the colon. Furthermore L1FLnI_1q23.1s showed a significant upregulation in peripheral blood mononuclear cells (PBMCs) of PLWH when compared to uninfected controls suggesting a common mechanism of differential ERE expression in the colon and PBMC. INTERPRETATION: ERE activity has been largely understudied in genomic characterizations of human pathologies. We show that the activity of certain EREs in the colon of PLWH is deregulated, supporting our hypotheses that their underlying activity could function as (bio)markers and potential mediators of pathogenesis in HIV-1 reservoirs. FUNDING: US NIH grants NCI CA260691 (DFN) and NIAID UM1AI164559 (DFN).

Ribosomal profiling of human endogenous retroviruses in healthy tissues.

Human endogenous retroviruses (HERVs) are the germline embedded proviral fragments of ancient retroviral infections that make up roughly 8% of the human genome. Our understanding of HERVs in physiology primarily surrounds their non-coding functions, while their protein coding capacity remains virtually uncharacterized. Therefore, we applied the bioinformatic pipeline "hervQuant" to high-resolution ribosomal profiling of healthy tissues to provide a comprehensive overview of translationally active HERVs. We find that HERVs account for 0.1-0.4% of all translation in distinct tissue-specific profiles. Collectively, our study further supports claims that HERVs are actively translated throughout healthy tissues to provide sequences of retroviral origin to the human proteome.

Locus specific human endogenous retroviruses reveal new lymphoma subtypes.

The heterogeneity of cancers are driven by diverse mechanisms underlying oncogenesis such as differential 'cell-of-origin' (COO) progenitors, mutagenesis, and viral infections. Classification of B-cell lymphomas have been defined by considering these characteristics. However, the expression and contribution of transposable elements (TEs) to B cell lymphoma oncogenesis or classification have been overlooked. We hypothesized that incorporating TE signatures would increase the resolution of B-cell identity during healthy and malignant conditions. Here, we present the first comprehensive, locus-specific characterization of TE expression in benign germinal center (GC) B-cells, diffuse large B-cell lymphoma (DLBCL), Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt lymphoma (BL), and follicular lymphoma (FL). Our findings demonstrate unique human endogenous retrovirus (HERV) signatures in the GC and lymphoma subtypes whose activity can be used in combination with gene expression to define B-cell lineage in lymphoid malignancies, highlighting the potential of retrotranscriptomic analyses as a tool in lymphoma classification, diagnosis, and the identification of novel treatment groups.

Paxlovid-Induced Tacrolimus Toxicity in the Treatment of COVID-19: A Case Report.

PaxlovidTM (nirmaltrelvir/ritonavir) received emergency use authorization from the Food and Drug Administration (FDA) in December 2021 to treat coronavirus disease 2019 (COVID-19). Given the actions of Paxlovid on cytochrome P450-3A4 (CYP3A4) enzymes, it is imperative to check for potential drug-drug interactions before prescribing. We describe a case in which the common emergency department presentation of generalized weakness was found to be caused by interactions between Paxlovid and a patient's home medications resulting in tacrolimus toxicity.

Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.

Transposable elements (TEs) are mobile genomic sequences that encompass roughly 50% of the human genome. Class 1 TEs, or "retrotransposons," mobilize through the production of an RNA intermediate that is then reverse transcribed to form complementary DNA (cDNA) molecules capable of genomic reinsertion. While TEs are traditionally silenced to maintain genomic integrity, the recognition of immunostimulatory cues, such as those provided by microorganisms, drastically alters host transcription to induce the differential expression of TEs. Emerging evidence demonstrates that the inducible production of TE cDNA is not an inert phenomenon but instead has been coopted by host immunity to facilitate cross talk between host and constituents of the microbiota by agonizing intrinsic antiviral receptors. Here, we demonstrate that immunostimulation of toll-like receptor 4 (TLR4) with lipopolysaccharide (LPS) and TLR5 with bacterial flagella (FLA) alters the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Next, we demonstrate that reverse transcriptase inhibitor (RTi) delivery ameliorates the acute production of the proinflammatory cytokine "tumor necrosis factor alpha" (TNF-α) in response to FLA in a monocytic cell line (THP-1). Collectively, our findings demonstrate that TLR5-mediated cross talk between the host and microbiota is partially dependent on the reverse transcription (RT) of retrotransposons. IMPORTANCE The microbiota is a potent reservoir of immunostimulatory and immunosuppressive motifs that fundamentally shape host immunity. Despite broad associations between microbial composition and host immunity, the mechanisms underlying host microbiota-induced immunoregulation remain poorly defined. Here, we demonstrate a novel mechanism by which motifs overabundant during dysbiotic conditions influence host immunity through the upregulation of endogenous RT to produce motifs that agonize antiviral receptors.

Natural Products from Microalgae with Potential against Alzheimer's Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors.

In recent years, many new enzymes, like glutaminyl cyclase (QC), could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme-inhibiting properties of natural substances are becoming increasingly important. In different studies, the pathophysiology connection of QC to various diseases including Alzheimer's disease (AD) was described. Algae are known for the ability to synthesize complex and highly-diverse compounds with specific enzyme inhibition properties. Therefore, we screened different algae species for the presence of QC inhibiting metabolites using a new "Reverse Metabolomics" technique including an Activity-correlation Analysis (AcorA), which is based on the correlation of bioactivities to mass spectral data with the aid of mathematic informatics deconvolution. Thus, three QC inhibiting compounds from microalgae belonging to the family of sulfolipids were identified. The compounds showed a QC inhibition of 81% and 76% at concentrations of 0.25 mg/mL and 0.025 mg/mL, respectively. Thus, for the first time, sulfolipids are identified as QC inhibiting compounds and possess substructures with the required pharmacophore qualities. They represent a new lead structure for QC inhibitors.

Intra-osseous gout in a diabetic patient.

UNLABELLED: The following case is an interesting presentation of gout and its long-term affects in a diabetic individual. The patient initially presented with ankle pain and, after radiographic examination, a suspicious lytic lesion in the talus and a fracture of the medial malleolus were identified. A full workup with bone biopsy was undertaken and, although the patient did not present in the typical fashion, gout was ultimately diagnosed. Based on our experience with this patient, we recommend that gout be included in the list of differential diagnoses in diabetic patients with ankle pain and radiographic evidence of articular and bone destruction. The diagnosis and treatment of gout are addressed in this paper as well. LEVEL OF CLINICAL EVIDENCE: 4.