Biology subjects

Rokx, C.

Publications and source records attributed to Rokx, C..

7 recordsLinked to original sources

bioRxiv2026

Viral persistence and antiretroviral therapy shape systemic immune aging in treated HIV infection

Chronic infections can reshape immune system homeostasis, yet how persistent viral infections influence immune aging remains poorly understood. People living with HIV provide a unique model to investigate how long-term viral persistence affects immune aging despite effective antiretroviral therapy. Here, we characterize immune aging by integrating plasma proteomics with epigenetic and transcriptional profiles of circulating immune cells across large cohorts of treated individuals with HIV. We find that immune aging is markedly accelerated compared with healthy individuals and parallels established DNA methylation-based aging clocks. Accelerated immune aging is strongly associated with signatures of immunosenescence and correlates with the size of the latent HIV reservoir, suggesting a persistent imprint of viral persistence on immune aging trajectories. Notably, exposure to specific antiretroviral agents, particularly nucleoside reverse transcriptase inhibitors, is associated with reduced immune aging and suppression of age-associated immune gene programs. Together, these findings identify chronic viral persistence as a driver of systemic immune aging and indicate that antiretroviral therapy can partially modulate immune aging programs.

immunology↗

bioRxiv2026

Larger inducible reservoir and higher abundance of exhausted CD8+ T cells in people treated after late versus non-late diagnosis of chronic HIV one year after ART initiation

Background Despite effective antiretroviral therapy, HIV-1 remains a global health challenge. Most people living with HIV (PWH) are diagnosed in the chronic stage and around half are diagnosed late globally. Insight into the effect of time of diagnosis and therapy initiation on reservoir dynamics and immune reconstitution within the group with a chronic diagnosis is limited. Methods In this prospective cohort study, PWH diagnosed during the chronic stage (from Fiebig VI) were stratified into late (<350 CD4+ T cells/mm3 or an AIDS-defining illness) or non- late diagnosis subgroups. We analyzed the viral reservoir by IPDA, SQuHIVLa and FISH-Flow, and the immune compartment with the HIV-specific AIM assay and a 45-color spectral flow cytometry panel in the first year after ART initiation. Findings Although proviral DNA decreased during the first year of ART, the inducible reservoir remained stable. One year after ART initiation, exhausted CD8+ T cell abundance correlated significantly with CD4+ T cell count pre-ART. PWH with a late diagnosis had a significantly higher inducible reservoir and lower CD4+ T-cell counts than the non-late HIV diagnosis subgroup. Moreover, the subgroup with a late diagnosis showed higher abundance of exhausted CD8+ T cells, higher expression of activation/exhaustion markers, and lower naive CD4+ T-cell abundance than the non-late diagnosis subgroup. Interpretation Our results show that late diagnosis is associated with a persistently higher inducible viral reservoir and impaired immune recovery. These findings underline the importance of early diagnosis and treatment, and rationalize the use of late diagnosis as a covariate in future cure and reservoir studies.

immunology↗

bioRxiv2025

HIV-specific CD8+ T-cell responses soon after treatment initiation during acute HIV infection are associated with viral reservoir decline

Antiretroviral therapy (ART) initiated in the acute phase of HIV infection (AHI) results in a smaller viral reservoir. However, the impact of early HIV-specific T-cell responses on long- term reservoir dynamics is less well characterized. Therefore, we measured the size of the viral reservoir and functionality of HIV-specific CD8+ T-cell responses after the acute phase at 24 and 156 weeks after ART initiation in individuals who started treatment during AHI. A significant reduction in total and defective HIV DNA and a trend towards a reduction in intact HIV DNA were observed between 24 and 156 weeks. Functional CD8+ T-cell responses against HIV peptides Env, Gag, Nef, and Pol were maintained over three years after treatment initiation. The proliferative capacity of HIV-specific CD8+ T cells at 24 weeks of ART was predictive of the degree of reduction in total and defective HIV DNA between 24 and 156 weeks, suggesting HIV-specific CD8+ T-cells may at least partially drive the decline of the viral reservoir. Therefore, enforcing HIV-specific immune responses as early as possible after diagnosis of AHI should be a central focus of HIV cure strategies.

immunology↗

bioRxiv2021

dCas9 targeted chromatin and histone enrichmentfor mass spectrometry (Catchet-MS) identifies IKZF1as a novel drug-able target for HIV-1 latency reversal

A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to describe the protein composition of the latent and activated HIV-1 5LTR. Catchet-MS identified known and novel latent 5LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs that, by targeting IKZF1 for degradation, reverse HIV-1 latency in CD4+T-cells isolated from virally suppressed people living with HIV-1. One Sentence SummarydCas9 targeted chromatin and histone enrichment for mass spectrometry (Catchet-MS) led to the identification of IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

molecular biology↗

bioRxiv2020

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work we demonstrate the effect of DEAD-box polypeptide 3, X-Linked (DDX3) inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). RNA sequencing analysis revealed that while overall gene expression was minimally dysregulated, DDX3 inhibition in independent donor CD4+ T cells led to significant downregulation of BIRC5 and HSPB1A, genes critical to cell survival during HIV-1 infection. We used single-cell FISH-Flow technology to characterise latency reversal and the contribution of viral RNA to inducing cell death; pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3, upregulation of IFN{beta} and selective induction of apoptosis in viral RNA-expressing CD4+ T cells from PLWHIV but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV in an in vitro culture model over five days resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir as determined by quantitation of CA HIV-1 RNA, by TILDA, as well as by FISH-Flow technology. Our data support the translation of DDX3 inhibitor class compounds into HIV-1 curative strategies and provide proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards elimination of the inducible reservoir.

microbiology↗

bioRxiv2020

SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

Effective clinical intervention strategies for COVID-19 are urgently needed. Although several clinical trials have evaluated the use of convalescent plasma containing virus-neutralizing antibodies, the effectiveness has not been proven. We show that hamsters treated with a high dose of human convalescent plasma or a monoclonal antibody were protected against weight loss showing reduced pneumonia and pulmonary virus replication compared to control animals. However, a ten-fold lower dose of convalescent plasma showed no protective effect. Thus, variable and relatively low levels of virus neutralizing antibodies in convalescent plasma may limit their use for effective antiviral therapy, favouring concentrated, purified (monoclonal) antibodies.

microbiology↗

bioRxiv2019

Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb and reverses HIV-1 latency

A leading pharmacological strategy towards HIV cure requires "shock" or activation of HIV gene expression in latently infected cells with Latency Reversal Agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs we used fungal secondary metabolites (extrolites) as a source of bio-active molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the P-TEFb inhibitory 7SK snRNP complex to be significantly reduced upon GTX treatment of independent donor CD4+T cells. GTX disrupted 7SK snRNP, releasing active P-TEFb, which then phosphorylated RNA Pol II CTD, inducing HIV transcription. Our data highlight the power of combining a medium throughput bioassay, mycology and orthogonal mass spectrometry to identify novel potentially therapeutic compounds.

molecular biology↗