The pleural tuberculosis–associated microenvironment promotes HIV-1 persistence by impairing CD8+ T cell–mediated viral control
Samantha Cronin, Jennifer Simpson, Andrea Pereyra-Casanova, Yuchen Li, Josefina Marín-Rojas, Freja A. Warner van Dijk, Katie Fisher, Daniel J. Buffa, Hafsa Rana, Zoï Vahlas, Joaquina Barros, Mariano Maio, Thomas R. O’Neil, Kirstie M. Bertram, Eunok Lee, Najla Nasr, Andrew N. Harman, Gabriela Turk, Maria Florencia Quiroga, Anthony D. Kelleher, Christel Vérollet, Luciana Balboa, Sarah Palmer, Gabriel Duette
Samantha Cronin, Jennifer Simpson, Andrea Pereyra-Casanova, Yuchen Li, Josefina Marín-Rojas, Freja A. Warner van Dijk, Katie Fisher, Daniel J. Buffa, Hafsa Rana, Zoï Vahlas, Joaquina Barros, Mariano Maio, Thomas R. O’Neil, Kirstie M. Bertram, Eunok Lee, Najla Nasr, Andrew N. Harman, Gabriela Turk, Maria Florencia Quiroga, Anthony D. Kelleher, Christel Vérollet, Luciana Balboa, Sarah Palmer, Gabriel Duette
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Research Article AIDS/HIV Immunology Infectious disease

The pleural tuberculosis–associated microenvironment promotes HIV-1 persistence by impairing CD8+ T cell–mediated viral control

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1. This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are not completely understood. To address this knowledge gap, using pleural effusion samples from people living with HIV-1 and TB, we investigated how the HIV-1 genetic landscape and the anti–HIV-1 immune response are impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell–mediated antiviral response at this site of HIV-1/Mtb coinfection. Moreover, efficient CD8+ T cell activation was inhibited by lipids present in the TB-associated pleural effusion. These findings indicate that this immune microenvironment induced by TB promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in people living with HIV-1 and TB.

Authors

Samantha Cronin, Jennifer Simpson, Andrea Pereyra-Casanova, Yuchen Li, Josefina Marín-Rojas, Freja A. Warner van Dijk, Katie Fisher, Daniel J. Buffa, Hafsa Rana, Zoï Vahlas, Joaquina Barros, Mariano Maio, Thomas R. O’Neil, Kirstie M. Bertram, Eunok Lee, Najla Nasr, Andrew N. Harman, Gabriela Turk, Maria Florencia Quiroga, Anthony D. Kelleher, Christel Vérollet, Luciana Balboa, Sarah Palmer, Gabriel Duette

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Figure 8

TB-PE–derived lipids accumulate in CD8+ T cells and inhibit T cell activation.

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TB-PE–derived lipids accumulate in CD8+ T cells and inhibit T cell activ...
(A) Dot plot illustrating lipid-associated pathways upregulated in TB-PE–exposed resting CD8+ T cells. (B) Heatmap presenting normalized expression values of lipid-associated genes between unstimulated control and TB-PE–exposed cells. (C) Dot plot illustrating upregulated lipid-associated pathways in CD8+ T cells stimulated with anti-CD3/CD28 antibodies exposed to TB-PE when compared with control CD8+ T cells. (D) Heatmap of normalized expression values of lipid-associated genes between anti-CD3/CD28–treated control and TB-PE–exposed CD8+ T cells. (E and F) Representative images at ×40 (E) and ×100 (F) original magnification of neutral lipid staining in CD8+ T cells in the presence and absence of TB-PE. Scale bars: 20 μm (E), 4 μm (F). (G) Quantification of BODIPY mean fluorescence intensity (MFI) between control and TB-PE–exposed CD8+ T cells. (H) Top: Oxidative phosphorylation measured as oxygen consumption rate (OCR; left) and mitochondria-dependent ATP production (right). Bottom: Glycolysis measured as proton efflux rate (PER; left) and glycolysis-dependent ATP production (right). Olig, oligomycin; Rot, rotenone; AA, antimycin A. (I) Proportion of CD69+ (top) and CD25+ (bottom) cells stimulated with anti-CD3/CD28 antibodies in the presence of either pooled TB-PE (red), the lipid fraction (Lip-PE) (red), lipid vehicle (gray), the polar fraction (PF-PE) (red), or the polar fraction vehicle (gray). Data are shown as mean ± SD. Each dot represents an independent donor. Statistical significance was determined by paired 2-tailed t test or 1-way ANOVA followed by Tukey’s HSD post-test. **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.