TB co-infection fuels HIV reservoir diversity and drug resistance

HIV can be suppressed by antiretroviral therapy (ART), but a long-lived reservoir of latent virus allows HIV to persist even when treatment reduces active replication. Tuberculosis (TB) and latent TB infection (LTBI) are common in many parts of the world, and TB co-infection can change immune responses and influence how HIV behaves in the body. To better understand this interaction, Vainav Patel and colleagues studied how TB and LTBI affect HIV reservoirs, viral diversity, and the emergence of drug resistance in people who had not yet started ART. The team examined samples from 90 ART-naive individuals infected with HIV-1C, grouping them by IGRA and clinical TB diagnosis into HIV+LTBI−, HIV+LTBI+, and HIV+TB+ categories. From each participant they isolated plasma and PBMCs to extract viral RNA and DNA. They quantified total proviral DNA using gag PCR and amplified full-length env and pol genes for sequencing. Sequencing was performed on ONT and Illumina platforms, and subsequent analyses compared viral populations across compartments and TB status to reveal how TB co-infection might shape HIV persistence.

The study combined molecular and computational tools to compare proviral load, immune associations, viral diversity and drug resistance. Proviral DNA measures showed no statistically significant differences between HIV+LTBI−, HIV+LTBI+, and HIV+TB+ groups, although HIV+TB+ individuals trended toward higher levels. Correlation analyses picked up immune patterns: HIV+LTBI+ individuals had positive correlations with immune activation and PD-1 expression. Longitudinal follow-up after ART initiation found a modest decline in proviral load but persistence of proviral DNA for up to 18–20 months with evidence of low-level ongoing viral replication. For drug resistance, pol sequences were analyzed by Stanford HIVdb with a threshold mutation frequency of ≥10%, revealing a 33% prevalence of Drug Resistance Mutations (DRMs) among ART-naive participants, with higher occurrence in the HIV+LTBI+ group. Of the DRMs identified, 38% (5/13) in PBMC-derived sequences and 71% (5/7) in plasma-derived sequences were polymorphic mutations associated with Integrase strand transfer inhibitors (INSTIs). DRMs were highly concordant between plasma and PBMC-derived viruses. Full-length env phylogenetic analysis, aligned with an Indian Subtype C reference sequence and visualized using ggplot2, showed overlapping viral populations across the three groups and greater diversity in PBMCs compared to plasma.

Taken together, these findings suggest that TB co-infection and LTBI can shape HIV reservoir behavior, viral diversity, and the emergence of drug resistance even before ART exposure. Although overall proviral loads were comparable across groups, the immune activation associated with LTBI and the microenvironments created by TB granulomas may provide niches that favor viral diversification and the appearance or transmission of resistance-associated polymorphisms, including changes linked to INSTIs. The high concordance of DRMs between plasma and PBMC compartments highlights that resistance detected in one compartment likely reflects systemic viral populations, supporting the value of multi-compartment analysis. Because the study observed transmitted or pre-existing resistance in ART-naive individuals, the authors underscore the importance of baseline screening for DRMs and sustained surveillance, particularly in TB-endemic settings. In practical terms, these results point to the need for careful monitoring of drug resistance and viral diversity when treating people with or at risk for TB and LTBI, so that ART strategies remain effective.