HIV disrupts lung immune architecture in tuberculosis granulomas

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading infectious killer worldwide, and people living with HIV face a higher risk of TB even when taking antiretroviral therapy (ART). To better understand what happens inside the lung lesions called granulomas where TB bacteria are contained or allowed to grow, researchers led by Jessica Marie Medrano compared granulomas in a controlled animal model. They used macaques co-infected with Mtb and simian immunodeficiency virus (SIV) — a stand-in for human HIV — and examined animals with and without ART. The team applied spatial transcriptomics, a technology that maps which genes are active and where they are located within tissue sections, to compare the cellular and molecular organization of granulomas across these different infection states. By focusing on spatial patterns, rather than averaging signals across whole lesions, the researchers could see how immune cells are arranged and how they communicate in tissues that are coping with Mtb alone or with SIV present. The study set out to reveal whether the immune geography of granulomas is changed by SIV and whether ART can restore normal patterns.

Using spatial transcriptomics on granulomas from macaques infected with Mtb alone, SIV/Mtb, and SIV/ART/Mtb, the researchers mapped where different immune programs were active within the lesions. In Mtb-only granulomas they observed spatially differentiated transcriptional profiles: myeloid cells were concentrated in an inner ring and showed enrichment for metabolic and antimicrobial pathways, while T cell costimulatory/activation pathways were enriched in an outer ring. Those clear, organized patterns were disrupted in SIV/Mtb granulomas. The SIV/Mtb lesions lost the spatial segregation and instead showed higher enrichment in type I IFN pathways compared to Mtb-only granulomas. Granulomas from SIV/ART/Mtb animals showed an intermediate transcriptional pattern that did not return to the Mtb-only organization, even though these ART-treated animals lacked evidence of viral replication. Across co-infected groups, cell-cell communication was reduced, indicating fewer or altered signaling interactions among immune cells within granulomas.

Taken together, these results suggest that SIV — and by implication HIV — disrupts the finely tuned, spatially organized immune functions of pulmonary granulomas that are important for controlling Mtb. The loss of inner-ring myeloid antimicrobial programs and outer-ring T cell activation, and the rise in type I IFN signatures in co-infected granulomas, point to a rewiring of local immunity that could undermine containment of the bacteria. Importantly, ART did not fully restore the normal granuloma architecture: SIV/ART/Mtb granulomas remained transcriptionally different from Mtb-only lesions despite suppressed viral replication. This helps explain why people living with HIV continue to have elevated TB risk even with widespread ART use. The findings underline that restoring viral suppression alone may not be sufficient to reestablish the spatial immune networks within granulomas, and that future work should consider how to recover or compensate for these local immune disruptions to improve TB outcomes in HIV-affected populations.