Biology subjects

Melo, C.

Publications and source records attributed to Melo, C..

3 recordsLinked to original sources

bioRxiv2026

HIV broadly neutralizing antibodies with enhanced Fc-CD16 affinity increase NK cell ADCC even with limited envelope binding

The persistence of latent HIV-1 reservoirs remains the primary barrier to a cure. Shock and kill strategies aim to reactivate these reservoirs and eliminate them via effector cells, such as Natural Killer (NK) cells. However, chronic infection leaves NK cells exhausted. In this study, we investigated the interplay between cytokine-mediated NK cell activation and antibody-dependent cellular cytotoxicity (ADCC) across diverse HIV-1 subtypes. We demonstrated that while cytokine stimulation enhanced natural cytotoxicity, it simultaneously induces shedding of the Fc receptor CD16 via the metalloproteinase enzyme ADAM17. However, restoring CD16 expression through ADAM17 inhibition (TAPI-1) did not improve ADCC, suggesting that CD16 surface levels in NK cells is not the only limiting factor. On the other hand, Fc-engineered broadly neutralizing antibodies (bNAbs) with increased CD16 affinity, in particular LPLIL and GASDALIE, significantly enhance ADCC across the six different HIV-1 subtypes, regardless of NK cells activation, CD16 downregulation or limited surface Envelope expression in CD4T cells. These findings suggest that enhancing receptor affinity of bNAbs can bypass viral immune evasion and NK cell exhaustion, supporting their potential incorporation into HIV cure strategies. ImportanceEradicating latent HIV reservoirs remains a global health priority, as it would liberate millions of people living with HIV (PLWH) from the economic and physiological burdens of lifelong antiretroviral therapy (ART). By utilizing a primary human cell model that resembles in vivo conditions across diverse viral strains, we identified that simply preventing CD16 receptor shedding from NK cells is insufficient to improve HIV-1 clearance. Instead, we demonstrated that enhancing the binding of antibodies to the CD16 receptor enables NK cells to overcome viral immune evasion and the loss of CD16 expression. This allows for potent elimination of infected cells through antibody-dependent cellular cytotoxicity (ADCC). These findings provide a clear strategy for designing more effective "kill" components in future therapeutic strategies.

immunology↗

bioRxiv2024

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

developmental biology↗

bioRxiv2017

Zika virus infection induces synthesis of Digoxin in glioblastoma cells

Recently, microcephaly cases have increased in Americas and have been matter of concern due to Zika virus (ZIKV) recent outbreak. Previous studies have shown that ZIKV-infected progenitor neuronal cells present morphological abnormalities and increased rates of cell death, which may be indicators of microcephaly causes. As recent studies indicate Zika virus tropism for brain cells, how would a glioblastoma (GBM) lineage behave under ZIKV infection, considering GBM the most common and malignant brain tumor in adults, presenting extreme chemoresistance and high morbidity and mortality rates? The current trend of using genetically engineered oncolytic pathogens as a safe way to eliminate tumors is under development, with trials already in course. Therefore, the present study evaluated the possible oncolytic effects and metabolomic alterations of Zika virus infection at human malignant M059J glioblastoma cells. Microscopic evaluation was performed using optical microscopy, which showed cytopathic effects induced by ZIKV at GBM cells. For the metabolomics study, both control and infected cell cultures were submitted to MALDI-MSI analysis. Mass spectrometry data were submitted to PLS-DA statistical analysis, and distinct biomarkers were elected for each infected groups. This study brings light to unexpectedly induced metabolic changes, as endogenous Digoxin as important biomarker for ZIKV-GBM group, associated with cytopathic effects induced by viral infection. These results evidences that genetically engineered ZIKV might be a potential new strategy for neural cancer management through the induction of endogenous digoxin synthesis in glioblastoma cells.

neuroscience↗