Higher Clostridia Expression Is Associated with Integrase Strand Transfer Inhibitor Treatment in People Living with Human Immunodeficiency Virus

Abstract

Human immunodeficiency virus (HIV) causes gut dysbiosis, exacerbating chronic inflammation and immune dysfunction. Antiretroviral therapies (ART) reduce viral replication and slow disease progression, yet conventional antiretroviral drug classes can contribute to further dysregulation of the gut microbiota through polymerase– or protease–inhibition. Integrase strand transfer inhibitors (INSTIs), a novel ART class, target HIV integrase, preventing viral DNA integration, potentially reducing side effects associated with other ART classes. We analyzed a dataset by Taylor et al. (2020) (accession: PRJEB38909) of 16S rRNA sequences from 488 fecal samples of people living with HIV (PLWH), to investigate the impact of INSTI on gut microbiome diversity and composition. We observed significant differences in beta diversity associated with both HIV status and INSTI treatment, but no differences in alpha diversity.  Five core microbiome genera and three indicator species were identified in INSTI+ individuals, both notably enriched in the Clostridia class. Differential abundance analysis revealed specific genera within the Clostridia class significantly upregulated in INSTI+ individuals. Functional pathway analysis indicated downregulation of microbial pathways related to methanogenesis and archaeal lipid biosynthesis. Machine learning models, k-nearest neighbors and random forest moderately predicted INSTI status based on microbiome composition and host metadata, with the random forest demonstrating superior predictive performance. Our findings highlight INSTIs' nuanced effects on gut microbiome composition and functionality, suggesting potential clinical implications for alleviating HIV-associated gut dysbiosis. Given the complexity and combinatorial nature of ART regimens, further analysis should examine how INSTIs interact with specific ART drug classes to influence microbiome dynamics.