Biology subjects

Katsikis, P. D.

Publications and source records attributed to Katsikis, P. D..

6 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↗

bioRxiv2026

Prime-Target neoantigen vaccination unleashes unprecedented T cell immunity within ''cold'' immunosuppressive tumors

"Cold" immunosuppressive solid tumors are hard-to-treat cancers that are non-responsive to immunotherapies. Their immunosuppressive tumor microenvironment (TME) excludes and inhibits T cells and thereby hampers the therapeutic efficacy of cancer vaccines and immune checkpoint blockade. To overcome this, we employed a "Prime-Target" (P/T) neoantigen vaccination strategy that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations to first prime potent systemic neoantigen-specific T cell immunity and then trigger intratumoral T cell recruitment. Using immunotherapy non-responsive murine tumor models with pronounced immunosuppressive TMEs, we demonstrate that P/T neopeptide vaccination resulted in extraordinary tumor control and TME remodeling. P/T vaccination elicited strong systemic anti-tumor responses as well as potent and rapid recruitment of clonal CD4+ Th1 and non-exhausted CD8+ T cells into tumors that carried novel T cell receptors (TCR) and were vaccine neopeptide-specific. Concurrently, P/T vaccination reshaped the TME by decreasing suppressive Treg and M2 macrophages, and dramatically increasing the ratio of effector T cells to Treg and M2 macrophages. Vaccination-induced tumor control was neopeptide-dependent and required concurrent IT administration of both neopeptides and adjuvants. Our study highlights P/T neoantigen vaccination as a promising strategy to overcome T cell exclusion within "cold" immunosuppressive solid tumors and thereby unleash unprecedented anti-tumor immunity.

immunology↗

bioRxiv2021

The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins

CD8+ T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that determine the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naive CD8+ T cells and the potency of the resulting cytotoxic lymphocytes. The RBP act in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-B, IRF8 and NOTCH1 transcription factors and cytokines, including IL2. Their absence in T cells, or the adoptive transfer of a small numbers of CD8+ T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals determining the speed and quality of the CD8 response.

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↗

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↗

bioRxiv2019

Hypothesis, analysis and synthesis: it's all Greek to me!

The linguistic foundations of science and technology have relied on a range of terms many of which are borrowed from ancient languages, a known but little researched fact from a statistical perspective. Precise definitions and novel concepts are often crafted with those -- frequently used -- terms, yet their etymology from Greek or Latin might not always be fully appreciated. Herein, we demonstrate that frequently used terms span almost the entire PubMed(R) database, while a handful of terms of Greek origin retrieve 80% of all entries. We argue that the etymology of those critical terms needs to be fully grasped to ensure correct use, in conjunction with other concepts. We further propose a number of terms for genomics, using prepositions that can accurately define subtle sub-disciplines of this ever-expanding field. Finally, we invite commentary by both the science community and the humanities, for possible adoption of suggested terms, not least to avoid inaccurate usage or inappropriate notions that may compromise clarity of meaning.

scientific communication and education↗