TB-associated microenvironment represents a barrier for HIV curative strategies

G. DUETTE; A. DE VRIES-EGAN; Z. VAHLAS ; C. MELUCCI ; P. PEREYRA GERBER; A. CZERNIKIER; A. PEREYRA CASANOVA; M. SHARABAS; G. TURK ; A. KELLEHER; C. VEROLLET ; L. BALBOA; S. PALMER

Brisbane

Conferencia; International AIDS Society (IAS) 2023, the 12th IAS Conference on HIV Science; 2023

Background: Tuberculosis (TB), the most frequent opportunistic co-infection in HIV-positive individuals, enhances the infectivity of each pathogen andworsens the clinical outcomes in persons living with HIV/TB. However, it is unclear how the TB-associated microenvironment affects HIV latency and theefficacy of CD8+ T-cells in eliminating HIV-infected cells. Therapeutically aspirated pleural effusions from TB participants (TB-PE) can reflect themicroenvironment found in human respiratory cavities impacted by TB infection. Therefore, we investigated the effects of TB-PE on latently HIV-infectedCD4+ T-cells and HIV-specific CD8+ T-cells.Methods: For HIV latency studies, CD4+ T-cells from 4 healthy donors were infected with a dual-fluorescent reporter HIV in the presence or absence of TB-PE.The proportion of latently and productively HIV-infected cells was quantified by flow cytometry. To test whether TB-PE affects HIV latency reversal, CD4+ Tcells from two HIV-positive donors on antiretroviral therapy were exposed to PMA with or without TB-PE. Levels of HIV reactivation were determined byquantifying unspliced HIV-RNA expression by qRT-PCR. The effector CD8+ T-cell response from 3 HIV-positive participants was assessed by measuringintracellular effector cytokine (IFN-γ/TNF-α) production and degranulation (CD107a/b) after stimulation with HIV-peptides in the presence or absence of TB-PE.In addition, the impact of TB-PE on the transcriptomic profile of CD8+ T-cells was characterized by RNAseq in cells from 3 healthy donors. Differential geneexpression analysis was performed to investigate the cellular pathways modulated by TB-PE.Results: The incubation with TB-PE significantly increased the proportion of latently HIV-infected cells ( p=0.012). In addition, PMA-induced latency reversalwas inhibited by TB-PE in CD4+ T-cells (p