Biology subjects

Gerlo, S.

Publications and source records attributed to Gerlo, S..

3 recordsLinked to original sources

bioRxiv2026

Multi-Omics Clustering Differentiates the Total and Intact HIV Reservoirs and Related Host Immune Mechanisms

HIV reservoirs are heterogeneous across individuals, yet host determinants of this variability remain unclear. Applying multi-omics clustering to 1,230 people with HIV, integrating omics and functional data from circulating immune cells (transcriptomics, DNA methylation, immune phenotyping, ex-vivo cytokine production capacity), plasma proteomics, and CD4+ T-cell reservoir measurements (total and intact HIV-DNA copies), revealed three immunologically distinct endotypes: All Low (low total/low intact reservoir size), All High (high total/high intact reservoir size) and Mixed (high total/low intact reservoir size). Per endotype, distinct immune landscapes were noticed in single-layer analyses as well as differences in clinical signatures. Applying non-linear machine learning across all layers, key predictors not captured by linear single-layer approaches showed IFN-{gamma} production and TCF7/AK5 expression across T-cell and NK-cell populations as well as IL-1{beta}/MCP-1 production after 24h stimulation and MAN1C1/EDAR expression on T-cell populations, linked to intact and total reservoir size, respectively. This host-virus integrative multi-omics framework provides a systems-level resource that may help to personalize reservoir-reducing intervention studies aiming for HIV cure and/or comorbidity reductions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/734029v4_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@16fded7org.highwire.dtl.DTLVardef@18f2e69org.highwire.dtl.DTLVardef@12ffc9borg.highwire.dtl.DTLVardef@17127cc_HPS_FORMAT_FIGEXP M_FIG a) Multi-omics clustering of 1,230 virally suppressed PLHIV identified three immunologically distinct endotypes: All Low (n=428), Mixed (n=483), and All High (n=280), with distinct total and intact HIV reservoir sizes. b) Single-layer analyses reveal characteristic immune landscapes: All Low Th1-skewed, naive T cells (immunophenotyping), high IFN-{gamma} production (7-day), downregulated Type I IFN pathways (bulk transcriptome); Mixed intermediate Th1/Th2, CD8 and CD4 effector memory T cells (immunophenotyping), IL-5 production (7-day), downregulated Type I IFN pathways (bulk transcriptome); All High Th2-skewed, CD4 effector memory T cells (immunophenotyping), high IL-5 production (7-day), upregulated Type I IFN pathways (bulk transcriptome). c) Endotypes carry distinct comorbidity burdens: All Low lower carotid plaque, AIDS-defining malignancies, and residual viremia; Mixed intermediate burden; All High highest carotid plaque, AIDS-defining malignancies, opportunistic infections, and residual viremia. d) Non-linear classification models (XGBoost) prioritize top host predictive markers: IFN-{gamma} response (7-day), TCF7 and AK5 expression in CD4/CD8 T-cells and NK-cells (characterize All Low; IL-1 response (24-hour), MAN1C1 and EDAR in CD4/CD8 T-cells, and MCP1 response (24-hour) characterize All High. Created in BioRender. C_FIG

immunology↗

bioRxiv2026

Broadly neutralizing antibody-secreting CAR-T cells elicit Fc-mediated effector functions in vitro and suppress HIV in humanized mice

Despite significant advances in antiretroviral therapy (ART) that have transformed human immunodeficiency virus (HIV) infection from a fatal diagnosis to a manageable chronic condition, the persistent viral reservoir necessitates lifelong treatment underscoring the critical need for curative interventions. Viral persistence within anatomically distinct reservoirs, coupled with HIV-associated immune dysregulation accentuates the need for innovative combination immunotherapies that can act through multiple mechanisms. We introduce the Hybrid chimeric antigen receptor (CAR) platform: a dual-function immunotherapy that combines the targeted cytotoxicity of CAR-T cells with the secretion of broadly neutralizing antibodies (bNAbs). This approach enables direct elimination of HIV-infected cells, neutralization of free virus and Fc-mediated effector recruitment. In vitro, Hybrid CAR-T cells eliminated HIV-infected CD4+ T cells while the secreted bNAbs neutralized HIV and mediated robust Fc-effector functions including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In humanized mice, Hybrid CAR-T treatment achieved more than a 9-fold reduction in plasma viremia, accompanied by a significant decrease in viral levels across tissues, with circulating bNAbs detected in plasma. Collectively, these findings highlight the potential of Hybrid CAR-T cells as a synergistic next-generation therapeutic that bridges cellular and humoral immunity, supporting their translational promise as a strategy toward functional HIV cure.

immunology↗

bioRxiv2023

Integrative assessment of total and intact HIV-1 reservoir by a five-region multiplexed Rainbow digital PCR assay

Persistent latent reservoirs of intact HIV-1 proviruses, capable of rebounding despite suppressive ART, hinder efforts towards an HIV-1 cure. Hence, assays specifically quantifying intact proviruses are crucial to assess the impact of curative interventions. Clinical trials have utilized two recent assays: intact proviral DNA assay (IPDA) and Q4PCR. While IPDA is more sensitive due to amplifying short fragments, it may overestimate intact fractions by relying only on two small regions. Q4PCR is sequencing-based and its performance might be subjected to bias against full-length proviruses. Leveraging digital PCR (dPCR) advancements, we developed the Rainbow 5-plex proviral HIV-1 DNA assay, assessing it with standard materials and samples from 69 PLWH. The Rainbow assay proved equally sensitive but more specific than IPDA, is not subjected to bias against full-length proviruses, enabling high-throughput quantification of total and intact reservoir size. This innovation offers potential for targeted evaluation and monitoring of rebound-competent reservoirs, contributing to HIV-1 management and cure strategies. TeaserThe 5 color HIV-1 Rainbow digital PCR assay offers a multi-level view on the HIV reservoir in one snapshot reaction.

molecular biology↗