Biology subjects

Gruters, R. A.

Publications and source records attributed to Gruters, R. A..

2 recordsLinked to original sources

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↗

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↗