CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

884

Persistence of PD-1+ Mtb-Specific CD4+ T Cells Is Associated With CAD During and After TB Treatment Manuel G. Feria Garzon 1 , Eduardo Ticona 2 , Cecilia Chang 3 , Wendy Guevara 2 , Anissa Moussa 1 , Alberto La Rosa 3 , Javier R. Lama 3 , Claire A. Chougnet 4 , Moises A Huaman 1 1 University of Cincinnati, Cincinnati, OH, USA, 2 Hospital Nacional Dos de Mayo, Lima, Peru, 3 Asociacion Civil Impacta Salud y Educacion, Lima, Peru, 4 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Background: Individuals who recovered from tuberculosis disease (post-TB) remain at increased risk of cardiovascular events and mortality. However, the underlying mechanisms of cardiovascular disease in post-TB remain unknown. Here, we aimed to characterize the immune profile of Mtb-specific CD4+ T cells in post-TB and explore their relationship with coronary artery disease (CAD). Methods: We conducted a cross-sectional study of individuals 40 to 70 years of age with latent TB infection (LTBI), TB patients on isoniazid/rifampin consolidation treatment (TB-on-treatment); and clinically-cured individuals within one year of TB treatment completion (post-TB) between March 2018 and October 2019. Participants completed a coronary tomography angiography to assess CAD and provided blood for immune profiling of Mtb-specific CD4+ T cells using flow cytometry. Mtb-specific T cells were defined based on IFN-γ, IL-2, or TNF-α intracellular cytokine production upon in vitro PBMC stimulation with CFP-10/ESAT-6 or Mtb-whole-cell-lysate. Results: 41 LTBI, 24 TB-on-treatment, and 11 post-TB participants without HIV were included in this analysis. After PBMC stimulation with Mtb-lysate, TB-on treatment and post-TB patients exhibited higher percentage of Mtb-specific CD4+ T cells compared to LTBI (1.35 vs. 1.55 vs. 0.69; p=0.006). The percentage and MFI of activation markers HLA-DR, CD38, and delta HLA-DR (CD4minusMtb) were higher on Mtb-specific CD4+ T cells from TB-on-treatment and post-TB patients upon CFP-10/ESAT-6 and Mtb-lysate stimulation. Compared to LTBI, percentage of KI-67 and PD1 expression on Mtb-specific CD4+ T cells were increased in TB-on-treatment and post-TB upon Mtb-lysate stimulation (Figure 1). Polyfunctionality analyses revealed that TB-on-treatment participants exhibited a higher percentage of Mtb-specific CD4+ T cells positive to ≥2 cytokines upon Mtb-lysate stimulation, compared LTBI and post-TB participants. TB-on-treatment and post-TB individuals with CAD had higher MFI of PD1 on Mtb-specific CD4+ T cells, compared to those without CAD (181.5 vs. 123; p=0.022). Similarly, MFI of PD1 on Mtb-specific CD4+ T cells from TB-on treatment and post-TB individuals positively correlated with CAD-RADS score (Spearman rho=+0.502; p=0.017). Conclusion: Despite clinical TB cure, individuals post-TB exhibited signs of persistent immune activation and exhaustion of their Mtb-specific CD4+ T cell population. PD1 expression on Mtb-specific CD4+ T cells was associated with CAD during TB treatment and post-TB.

885

Suppression of Immunoglobulin Production and Mortality in HIV Associated Cryptococcal Meningitis Ronan Doyle 1 , F. Kathryn Boyd 1 , David S. Lawrence 1 , Kwana Lechiile 2 , Tshepo B. Leeme 2 , Nabila Youssouf 3 , Thomas S. Harrison 4 , Cecilia Kanyama 5 , Mosepele Mosepele 6 , Henry C. Mwandumba 7 , Chiratidzo Ndhlovu 8 , James Scriven 9 , Joseph N. Jarvis 1 , for the AMBITION Study Group 1 London School of Hygiene & Tropical Medicine, London, United Kingdom, 2 Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana, 3 London School of Hygiene & Tropical Medicine, Blantyre, Malawi, 4 St George's University of London, London, United Kingdom, 5 University of North Carolina Project–Malawi, Lilongwe, Malawi, 6 University of Botswana, Gaborone, Botswana, 7 Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi, 8 University of Zimbabwe, Harare, Zimbabwe, 9 University of Birmingham, Birmingham, United Kingdom Background: Cryptococcal meningitis (CM) primarily affects those with advanced HIV disease. Regardless of antiretroviral therapy status, roughly 15-20% of those diagnosed with CM die within 2 weeks even with the best available antifungal treatment. Despite advances in the management of CM with combination antifungals, there is still a poor understanding of the possible compromised immune responses contributing to this high mortality. There have been very few studies in humans, and these have tended to focus on a handful of biomarkers. In this study, for the first time, we use whole transcriptome RNA sequencing to identify the gene expression signature in blood and CSF from those who died from CM compared to those who survived. Methods: We performed bulk RNA-sequencing on whole blood and CSF collected from the first 200 consecutively recruited participants with HIV and CM into the AMBITION-cm trial in Botswana, Zimbabwe and Malawi. After sequencing we analysed differential gene expression and Gene Ontology pathway analysis from 99 CSF and 162 blood samples comparing those who died within 2 weeks (CSF; n = 10, Blood; n = 18) to those that survived at 2 weeks (CSF; n = 89, Blood; n = 144). Results: We identified a robust transcriptional signature in the CSF where 1010 genes were significantly differentially expressed when comparing survivors to the deceased (Fig 1a). The majority of these differentially expressed genes (DEGs) were downregulated in participants who died within 2 weeks. Gene ontology analysis of these downregulated genes indicated that it was suppression of pathways associated with immunoglobulin production as well as complement and B cell activation that were all significantly associated with mortality (Fig 1b). From these pathways we identified 21 DEGs responsible for immunoglobulin production and structure expressed in participants that survived and absent in those that died. Analysis of whole blood did not reveal any significant transcriptional responses. Conclusion: This study is the first of its kind to identify a unique CSF transcriptional signature that differentiates CM survivors from deceased. This was unique to CSF and was not seen in blood. We found an impaired adaptive immune response and diminished B cell response that is common in advanced HIV disease and that may lead to an inability to clear the fungus. This work can now be applied to develop better prognostic tests and improve targeted treatments for severe CM and other neurological infections.

Poster Abstracts

CROI 2024 275