Background
The persistence of HIV-infected cells containing genetically-intact and replication-competent virus remains the main obstacle to achieving an HIV cure. Tuberculosis (TB) is the most prevalent opportunistic infection in people with HIV (PWH) but the impact of TB on the immune response to HIV, and the persistent HIV reservoir, is poorly understood. To address this issue, we studied the effect of TB/HIV coinfection on the persistence of cells infected with genetically-intact HIV. In addition, access to therapeutically aspirated pleural effusions (TB-PE) from persons living with HIV and TB allowed for a more in-depth analysis on the impact of the TB-microenvironment on HIV persistence and the functionality of anti-HIV CD8 T-cells.
Methods
We used full-length individual proviral sequencing (FLIPS) to quantify the frequency of genetically-intact HIV in peripheral blood mononuclear cells (PBMCs) from 3 PWH and 3 individuals with TB/HIV. In one participant with TB/HIV coinfection, mononuclear cells from TB-PE (PEMCs) and PBMCs were also sequenced using FLIPS to characterize the site of the co-infection. To evaluate the impact of the TB microenvironment on HIV-specific cytotoxicity, CD8 T-cells from 4 PWH were cocultured with autologous HIV-infected CD4 T-cells in the presence or absence of TB-PE. Moreover, the impact of TB-PE on the transcriptomic profile of CD8 T-cells was characterized by RNAseq in cells from 3 healthy donors.
Results
Our analysis revealed a 3.2-fold increase in the frequency of cells infected with genetically-intact HIV in individuals with TB/HIV coinfection compared to PWH. Notably, within the individual with TB/HIV, PEMCs exhibited a 15.5-fold increase of intact HIV-infected cells compared to PBMCs. Interestingly, CD8 T-cells exposed to TB-PE demonstrated a significantly diminished capacity to eliminate HIV-infected cells (p=0.0021). Transcriptomic analysis showed that TB-PE downregulated pathways related to T-cell activation and the inflammatory response.
Conclusions
These findings suggest that the TB-associated microenvironment hampers CD8 T-cell-mediated HIV control, promoting the persistence of genetically-intact HIV at the site of coinfection. This impaired cytotoxic response likely contributes to the persistence of the viral reservoir in the blood of individuals with TB/HIV coinfection. Our study underscores the significant challenge that TB poses to HIV curative strategies and highlights the need for targeted interventions for individuals living with HIV and TB.
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