Biology subjects

Sonnerborg, A.

Publications and source records attributed to Sonnerborg, A..

9 recordsLinked to original sources

bioRxiv2026

Exploring the molecular function of metabolites identified in Elite Controllers and their role in epithelial integrity and immune regulation

Despite advances in treatment, HIV-1 infection continues to remain a major global health challenge, prompting ongoing efforts to understand the mechanisms that enable natural viral suppression and immune control. Elite controllers (ECs), a rare subset of PLWH individuals, naturally suppress HIV-1 replication without antiretroviral therapy, highlighting the importance of host-related factors in viral control. Understanding the mechanisms underlying this unique phenotype is crucial for developing novel therapeutic strategies. Previous studies from our group identified certain EC-specific metabolites, called dipeptides (DPs), and investigated their antiviral properties. We hypothesize that these dipeptides may potentially affect epithelial barrier integrity by modulating the expression of tight junction proteins, which in turn influences the mucosal barrier function, a key factor in HIV-1 pathogenesis. Therefore, in this study we investigated the impact of ten EC-specific DPs on tight junction (TJ) gene and protein expression in epithelial models derived from the female reproductive and gastrointestinal tracts, where we observed enhanced expression of different TJ genes (CLDN1, CLDN3, CLDN4, CLDN7, CLDN14, TJP1, TJP2, OCLN) and proteins (CLDN1, CLDN7, and CLDN14), suggesting the potential influence of these dipeptides on epithelial barrier function. Furthermore, we also examined different proteomic profiles between dipeptide (WG)-treated HeLa CD4+ CCR5+ cells compared with the untreated ones, and observed significantly reduced abundance of pro-inflammatory proteins, such as RELB Proto-Oncogene (RELB), TNF--induced protein 1 (TNFAIP1), TNF receptor superfamily member 1A (TNFRSF1A), and IL-32, in dipeptide-treated cells; and increased expression of proteins associated with tissue homeostasis (SMAD family member 5 [SMAD5]), cellular proliferation (transforming growth factor {beta} receptor 3 [TGFBR3]), and epithelial integrity, like CD81. Interestingly, KEGG analysis revealed possible attenuation of NF-{kappa}B, MAPK, TNF, and JAK-STAT signaling pathways, along with the enrichment of mTOR and PI3K-AKT pathways in treated HeLa CD4+ CCR5+ cells. Overall, this study investigated the potential interplay between tight junction proteins and key signaling pathways involved in maintaining epithelial barrier integrity and modulating immune activation, potentially contributing to both HIV-1 control and to the chronic inflammation associated with infection.

molecular biology↗

bioRxiv2025

Single-Shot Design of a Cyclic Peptide Inhibitor of HIV-1 Membrane Fusion with EvoBind

HIV evades the immune system through rapid mutation of its surface proteins, particularly the envelope glycoprotein. However, the core mechanism of viral entry, CD4 binding and co-receptor engagement remains conserved. While therapies such as Lenacapavir represent important advances, the continued emergence of resistant strains will demand new and more adaptable treatment strategies. This challenge is not unique to HIV; future pandemics will likely present similar pressures, highlighting the need for drug design methods that are not only effective but also fast and scalable. Recent advances in protein structure prediction have transformed the landscape of therapeutic design, enabling the accurate modelling of target structures from sequence alone and now facilitating the development of novel therapeutics without prior structural data. EvoBind leverages these advances to rapidly generate cyclic peptide binders in a single design round, using only the amino acid sequence of a target protein. Cyclic peptides offer several advantages over traditional linear protein molecules, including increased stability, while their small size improves oral bioavailability and enables access to challenging binding sites. Here, we demonstrate the use of EvoBind to generate cyclic peptide binders against the HIV envelope protein gp41, which is essential for viral-host membrane fusion. Cell-based assays confirm potent inhibition of two different HIV-1 strains with no detectable toxicity. The combination of artificial intelligence-guided design and streamlined experimental validation can significantly accelerate therapeutic development, reduce costs, and provide timely solutions to the challenges posed by viral evolution and emerging global health threats.

pharmacology and toxicology↗

bioRxiv2021

Factors Associated with Emerging and Re-emerging of SARS-CoV-2 Variants

Global spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has triggered unprecedented scientific efforts, as well as containment and treatment measures. Despite these efforts, SARS-CoV-2 infections remain unmanageable in some parts of the world. Due to inherent mutability of RNA viruses, it is not surprising that the SARS-CoV-2 genome has been continuously evolving since its emergence. Recently, four functionally distinct variants, B.1.1.7, B.1.351, P.1 and CAL.20C, have been identified, and they appear to more infectious and transmissible than the original (Wuhan-Hu-1) virus. Here we provide evidence based upon a combination of bioinformatics and structural approaches that can explain the higher infectivity of the new variants. Our results show that the greater infectivity of SARS-CoV-2 than SARS-CoV can be attributed to a combination of several factors, including alternate receptors. Additionally, we show that new SARS-CoV-2 variants emerged in the background of D614G in Spike protein and P323L in RNA polymerase. The correlation analyses showed that all mutations in specific variants did not evolve simultaneously. Instead, some mutations evolved most likely to compensate for the viral fitness.

bioinformatics↗

bioRxiv2021

Cytotoxic lymphocytes target HIV-1 Gag through granzyme M-mediated cleavage

HIV-1 leads to progression to immunodeficiency and death of individuals who do not receive successful antiretroviral therapy. Initially, the hosts immune response controls the infection, but cannot eliminate the HIV-1 from the host. Cytotoxic lymphocytes are the key effector cells in this response and can mediate crucial antiviral responses through the release of a set of proteases called granzymes towards HIV-1-infected cells. However, little is known about the immunological molecular mechanisms by which granzymes could control HIV-1. Since we noted that HIV-1 subtype C (HIV-1C) Gag with the tetrapeptide insertion PYKE contains a putative granzyme M (GrM) cleavage site (KEPL) that overlaps with the PYKE insertion, we analyzed the proteolytic activity of GrM towards Gag. Immunoblot analysis showed that GrM could cleave Gag proteins from HIV-1B and variants from HIV-1C of which the Gag-PYKE variant was cleaved with extremely high efficiency. The main cleavage site was directly after the insertion after leucine residue 483. GrM-mediated cleavage of Gag was also observed in co-cultures using cytotoxic lymphocytes as effector cells and this cleavage could be inhibited by a GrM inhibitor peptide. Altogether, our data indicate towards a noncytotoxic immunological mechanism by which GrM-positive cytotoxic lymphocytes target the HIV-1 Gag protein within infected cells to potentially control HIV-1 infection. This mechanism could be exploited in new therapeutic strategies to treat HIV-1-infected patients to improve immunological control of the infection.

immunology↗

bioRxiv2021

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

microbiology↗

bioRxiv2020

Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death

Most Covid-19 victims are old and die from unrelated causes. Here we present twelve complete autopsies, including two rapid autopsies of young patients where the cause of death was Covid-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163+ macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothel, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced Covid-19 ARDS.

pathology↗

bioRxiv2020

Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who are able to suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naive viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into mechanisms governing EC status. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP while inflammation markers were increased in VP compared to EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared to HC and CCL20/CCR6 axis can play important role. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to control of viral replication. One Sentence SummaryHIV-1 elite controllers had a distinct lipid profile, reduced inflammation, and increased antioxidant defense that might contribute to elite control status.

microbiology↗

bioRxiv2020

Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19

ABSTRACTSARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. We systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in a large cohort of unexposed individuals as well as exposed family members and individuals with acute or convalescent COVID-19. Acute phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative family members and individuals with a history of asymptomatic or mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits robust memory T cell responses akin to those observed in the context of successful vaccines, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19 also in seronegative individuals.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2019

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active replication comprises only cells with intact provirus that can be reactivated. We confirmed that latently infected cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of viral latency during proviral chromatin maturation in cultures of primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.

microbiology↗