Bacteriophage therapy targeting microbiome in HIV/AIDS

Despite antiretroviral therapy (ART) effectively suppressing viral replication and reducing transmission risk, human immunodeficiency virus (HIV) infection still sustains cycles of chronic inflammation, immune dysfunction, and dysbiosis of microbiota, driving barrier disruption, microbial translocation, and systemic inflammation. These pathological states accelerate cluster of differentiation 4+ (CD4+) T cell depletion, contribute to viral persistence, and exacerbate the risk of death caused by complications. Current microbiome interventions, such as prebiotics and fecal microbiota transplantations (FMTs), exhibit limited efficacy in regulating HIV infection-associated chronic inflammation, immune dysfunction, and dysbiosis of microbiota due to transient colonization and poor pathogen specificity. Bacteriophages (phages), which are viruses that precisely target bacteria, represent a promising alternative to ameliorate these intervention deficiencies and to optimize microbiome modulation, especially in HIV patients. Their precise host range and genetic tractability enable targeted modulation of pathogenic, commensal, and pathobiontic microbiota, which in turn enhances immunity against imbalanced microbiome-associated diseases. In this review, we explored phage therapy’s potential to disrupt HIV-associated pathologies affecting the host microbiome. We elucidated the mechanisms by which phage therapy targeted dysbiotic bacteria in HIV and reviewed the supporting preclinical and early clinical evidence for its role in preventing acquisition, enhancing viral clearance, restoring immunity, and managing comorbidities. Finally, we analyzed the challenges in translating phage therapy into clinical practice, which mainly include phage selection, regulatory frameworks, and delivery systems, and evaluated potential solutions to address these challenges. Collectively, our review emphasized how phage therapy can bring a paradigm shift in HIV management, where integrating microbiome-immune crosstalk with virology and synthetic biology may enable a functional cure within the next decade.