Biology subjects

Torres-Ruiz, F.

Publications and source records attributed to Torres-Ruiz, F..

5 recordsLinked to original sources

bioRxiv2026

An eicosanoid-enriched follicular microenvironment shapes germinal centre immune dynamics in antiretroviral-treated PLWH

Delineating the follicular (F) cellular and molecular landscape in HIV infection is essential for understanding neutralizing antibody responses and HIV reservoir maintenance. Multiplex imaging analysis revealed a less differentiated profile for follicular helper CD4 T cells (TFH) and significantly increased follicular CD25lo/hiFoxp3hi T cells in lymph nodes (LNs) from antiretroviral treated (cART) compared to viremic (Vir) people living with HIV (PLWH). Spatial transcriptomics identified distinct inflammatory follicular microenvironments in Vir and cART LNs, characterized by interferon and eicosanoid enrichment, respectively. In an independent cohort, scRNA-sequencing analysis of LN-derived cells revealed an enrichment of eicosanoid-related pathways in follicular immune cell types in non-neutralizers compared to neutralizers PLWH. In vitro infection and in situ multimodal investigation of HIV DNA+ cell microenvironments suggested a potential role of PGE2/Eicosanoids in maintaining viral reservoirs in cART LNs. Our data highlight cellular and molecular factors that could regulate both antibody responses and viral reservoir persistence in PLWH.

immunology↗

bioRxiv2026

Plasma metabolomics reveals lipid-predominant metabolic disruptions in virologically suppressed people with HIV

People with HIV (PWH) on antiretroviral therapy (ART) experience excess morbidity and mortality from comorbidities including cardiovascular and metabolic disease, yet the biological mechanisms underlying these outcomes in virally suppressed PWH (VS-PWH) remain incompletely understood. We applied high-dimensional targeted plasma metabolomics to quantify 254 small molecules and 750 lipids across 49 classes in viremic PWH (Vi-PWH), VS-PWH, and people without HIV (PWoH), analyzed alongside multiple T cell metrics and plasma cytokine concentrations. Globally, the plasma metabolome of VS-PWH was indistinguishable from PWoH, while Vi-PWH exhibited substantial metabolic disruption characterized by depletion of phosphatidylcholines, sphingomyelins, and hexosylceramides alongside triglyceride accumulation, dysregulation of the tryptophan-kynurenine and arginine-citrulline axes, and elevations in diacetylated polyamines and N4-acetylcytidine. Ordinal trend analysis identified subtle but consistent residual alterations in VS-PWH, particularly within phosphatidylcholine and sphingomyelin classes, that correlated with elevated TNF and reduced CD4+ T cell counts and CD4/CD8 ratio. Together, these findings indicate that residual TNF-associated inflammation and incomplete T cell recovery continue to shape the plasma metabolome in treated HIV, identifying candidate biomarkers for further mechanistic and clinical investigation.

microbiology↗

bioRxiv2025

Selective infection and loss of PRDM1+ LN Tfh cells in uncontrolled HIV infection precludes formation of Tfh reservoirs under ART

The multifaceted and long-lived nature of HIV-1 reservoirs has proven to be a formidable obstacle in the development of a therapeutic cure of HIV-1. One of the major dimensions of the HIV-1 reservoir is its prevalence and persistence in tissue environments, including in lymph nodes (LN). Within LN, T follicular helper (Tfh) cells are widely considered as the dominant sub-reservoir in viremic people with HIV (PWH). However, whether Tfh cells survive to establish a reservoir in PWH undergoing suppressive antiretroviral therapy (ART) has remained controversial. To address these issues, we deeply phenotyped over 500,000 cells and identified over 2,000 HIV-1 infected cells by employing single-cell multiomics on LN from PWH during viremia and suppressed on ART. While we detected HIV-1 infected Tfh cells, the majority of infected cells during viremia and ART had non-follicular phenotypes and were instead heterogeneously distributed between various CD4+ T-cell subsets. Within-subset comparisons of HIV+ and HIV- cells revealed heightened activation signatures and altered cell cycle states during viremia, but largely similar features during ART. Furthermore, the comparison between viremia and ART in PWH highlighted a noncanonical Tfh subset - defined by high locus accessibility and transcription of PRDM1 - that is selectively depleted during viremia, recovers after ART, and is highly susceptible to infection in vitro. Our work suggests a revised direction for the HIV-1 cure field where a mandate of any comprehensive strategy will be to address the high proportional burden of non-follicular cells within the HIV reservoir.

immunology↗

bioRxiv2024

Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naive PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH-B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH.

immunology↗

bioRxiv2022

Extensive heterogeneity of the HIV-1 infected CD4+ T-cell reservoir revealed by single-cell viral ASAPseq

Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a major impediment for HIV cure research. To address this, we developed single-cell viral ASAPseq to precisely define the unperturbed peripheral blood HIV-infected memory CD4+ T cell reservoir from antiretroviral treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by novel and known surface markers within total and individual memory CD4+ T cell subsets. We further uncovered novel epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.

microbiology↗