Biology subjects

Castellvi, J.

Publications and source records attributed to Castellvi, J..

3 recordsLinked to original sources

bioRxiv2025

Induction of Resident Memory CD8+T cell Phenotypes to Eliminate the HIV reservoir

During analytical treatment interruption (ATI), failure to contain tissue HIV reservoirs remains a major barrier to remission. We conditioned peripheral blood mononuclear cells with cues that promote tissue-resident memory differentiation, aiming to reprogram HIV-specific CD8+T cells for these tissue microenvironments. Sequential IL-15/TGF-{beta}1-stimulation expanded proliferative CD103+CD39+ effector populations and restored polyfunctional HIV-specific CD8+T cell responses, irrespective of CD39 or PD-1 expression. Cytokine-stimulated CD8+T cells enhanced ex vivo elimination of the HIV reservoir, and within the induced effector pool, only CD69+ subsets expressing CD103+ or CD39+ eliminated intact HIV-1 genomes. Single-cell transcriptomics showed that IL-15/TGF-{beta}1 stimulation increased clonotypic diversity and expanded resident-like effector clusters with reduced immune-checkpoint receptor expression and augmented mitochondrial function, findings confirmed by flow cytometry. Engrafted recipients from a humanized mouse ATI model more effectively eliminated HIV+-reactivated cells after adoptive transfer of sequentially-treated CD8+T cells. Thus, IL-15/TGF-{beta}1-mediated CD8+T cell reprogramming represents a promising immunotherapy to enable immune control after ATI.

immunology↗

bioRxiv2025

Identification of the Inducible HIV reservoir in Tonsillar, Intestinal and Cervical Tissue Models of HIV Latency

HIV persists in diverse tissues, with distinct cellular reservoirs presenting a major barrier to a cure and requiring targeted therapeutic strategies to address this heterogeneity. Here, we developed tissue models of HIV latency using human tonsillar, intestinal and cervicovaginal tissues. These models revealed differential HIV infection across CD4+ T cell subpopulations, with ART partially restoring CD4+ T cells and reducing intact HIV DNA. T follicular helper cells (TFH CD69+ CCR7-) were the primary inducible reservoir in tonsils, while tissue-resident memory cells (TRM CD69+ CD49a+) dominated in the intestine. Identification of markers for inducible reservoirs revealed that CD69, CD45RO, and PD-1 were shared across tissues, while CXCR5 in the tonsils and CD49a in the intestine served as tissue-specific markers. Furthermore, using different latency reversal agents (LRAs) we found that Histone Deacetylase Inhibitors (HDACis) failed to induce HIV in any tissue, the SMAC mimetic AZD5582 was effective only in a resident-memory CD4+ T cell subpopulation in the intestine, and IL15 exhibited the broadest reactivation potential across tissues and CD4+ T subsets. These models recapitulate key aspects of HIV infection providing insights into the inducible reservoirs composition in different tissues and informing strategies for its elimination.

immunology↗

bioRxiv2018

Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4 activated macrophages. The recruitment of this signalling complex was mediated through K63-polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4 activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63-polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo. Altogether, we identified that MSR1 signals through JNK via K63-polyubiquitylation and provide evidence for the receptors involvement in macrophage polarization.

immunology↗