The Tuberculosis-Associated Microenvironment Promotes Viral Persistence in People Living with HIV and Tuberculosis

SAMANTHA CRONIN; ANDREA PEREYRA CASANOVA; ZOÏ VAHLAS; EUNOK LEE; KABE FISHER; ANNEKE DE VRIES-EGAN; MAYSSA SHARABA ; ANTHONY KELLEHER; CHRISTEL VÉROLLET; LUCIANA BALBOA; SARAH PALMER; GABRIEL DUETTE

Melbourne

Congreso; Australian Centre for HIV & Hepatitis (ACH4) Annual Scientific Conference 2023; 2023

Background Tuberculosis (TB), the most frequent opportunisBc coinfecBon in people living with HIV (PLWH), enhances the infecBvity of each pathogen and worsens the clinical outcomes in persons coinfected with HIV/TB. However, it remains unclear how the TB-associated microenvironment affects the efficacy of CD8 T-cells in eliminaBng HIV-infected cells and the persistence of the HIV reservoir, which remains the main barrier to an HIV cure. TherapeuBcally aspirated pleural effusions from TB paBents (TB-PE) can reflect the microenvironment in human respiratory caviBes impacted by TB infecBon. Therefore, we invesBgated the effects of TB-PE on the HIV reservoir and HIV-specific CD8 T-cell response.Methods To determine the impact of the TB microenvironment on the persistence of the HIV reservoir, we evaluated the effect of TB-PE on the cytotoxic funcBon of CD8 T-cells from 4 HIV-posiBve parBcipants. Briefly, the CD8 T-cells were expanded using a pool of HIV-pepBdes in the presence or absence of TB-PE and subsequently cocultured with autologous HIV-infected CD4 T-cells. Moreover, the impact of TB-PE on the transcriptomic profile of CD8 T-cells was characterized by RNAseq in cells from 3 healthy donors. DifferenBal gene expression analysis was performed to invesBgate the cellular pathways modulated by TB-PE. In addiBon, we performed full-length HIV DNA sequencing of mononuclear cells from pleural effusion (PEMCs) and blood (PBMCs) from one HIV/TB coinfected individual to explore the effect of the TB-associated microenvironment on the HIV reservoir. Results The CD8 T-cells from HIV-donors treated with TB-PE exhibited a reduced capacity to kill HIVinfected cells when compared to untreated cells (p=0.0021). Moreover, cellular pathways involved in T-cell acBvaBon and inflammatory response were downmodulated by TB-PE in CD8 T-cells. Our sequence analysis revealed a higher frequency of infected cells in the pleural effusion (PEMCs) (380/106 cells, 95% CI: 301.4-478.3) when compared to PBMCs (33.9/106cells, 95% CI: 27.0-42.5). In addiBon, PEMCs harboured a higher proporBon of geneBcallyintact HIV than PBMCs (40% vs 27%, respecBvely).Conclusion In conclusion, our results indicate that the TB-associated microenvironment contributes to poor CD8 T-cell-mediated viral control at the site of the coinfecBon, increasing the geneBcallyintact and potenBally replicaBon-competent HIV reservoir in HIV/TB co-infected individuals. These findings indicate that TB infecBon poses a significant barrier to HIV curaBve strategies for individuals living with both HIV and TB.