Past TB Linked to Lasting Epigenetic Signals in People with HIV

People who survive tuberculosis (TB) often face higher long-term risks for cancer, heart disease and neurological problems, and these risks are especially concerning for people with HIV (PWH). The biological mechanisms behind those longer-term risks are not well understood. In a pilot cross-sectional study led by Joseph Baruch Baluku, researchers looked for changes in DNA methylation (DNAm) — a chemical tag on DNA that can affect gene activity — in the blood of PWH with and without prior TB. The study analyzed blood from 30 PWH divided into three groups of 10: those with prior latent TB infection (LTBI), those with previously treated active TB, and those with no history of TB. The team used the Illumina MethylationEPIC BeadChip, a technology that surveys over 850,000 CpG sites across the genome, to look for patterns of DNAm that differed by TB history. By comparing these groups, the researchers aimed to identify epigenetic footprints left by prior TB that could point to pathways linking TB with later health problems.

The analysis applied functional enrichment using Gene Ontology, KEGG pathways, and gene set enrichment analysis with statistical significance set at a false discovery rate of <0.05. Comparing prior active TB to no TB, the study found 25,084 differentially methylated CpGs (dmCpGs) that corresponded to 8 differentially methylated regions (DMRs) in KCNC4-DT, GRAMD1C, ZNF44, FIGN, KCNN3, and PLA2G1B. In the LTBI versus no TB comparison there were 7,682 dmCpGs corresponding to 18 DMRs in SPATC1L, ZFP57, KCNN3, LRSAM1, PLEKHG5, MCF2L, BRSK2, SH3GL2, AP001468.58 and STK32C. Across both TB comparisons, DNAm changes were enriched in pathways tied to neurogenesis, neuron differentiation, glutamatergic synapse, and neuroactive ligand-receptor interactions; the LTBI group also showed enrichment in synaptic membrane and serotonergic synapse pathways. Cardiovascular pathways were specific to prior active TB, including vascular smooth muscle contraction, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Both TB groups showed enrichment in gene sets associated with lung, colorectal, gastric, and breast cancers, with additional cancer pathway enrichments differing between the two TB histories.

Taken together, these findings show that in PWH a history of TB—whether latent or previously treated active disease—is associated with widespread changes in blood DNA methylation that align with biological pathways linked to nervous system function, heart disease, and various cancers. The specific DMRs and gene names identified point to concrete genomic locations where epigenetic marks differ by TB history, and the pathway enrichments suggest that prior TB could leave lasting molecular footprints that relate to later health risks. The differences between prior active TB and LTBI — for example, cardiovascular pathway signals seen mainly after active TB, and serotonergic or synaptic signals more prominent in LTBI — hint that the form of prior infection may leave distinct epigenetic signatures. As a pilot cross-sectional study, these results are associative and would need replication and deeper follow-up, but they support the idea that epigenetic mechanisms may help explain TB-related long-term complications in people living with HIV.