Chronic inflammation in virus-suppressed people living with human immunodeficiency virus infection: A microbiology-oriented perspective on gut barrier failure, microbial translocation, and immune activation.

Potent antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection into a chronic manageable condition; however, many people living with HIV (PLWH) exhibit persistent immune activation and inflammation despite long-term virological suppression. Residual inflammation is strongly associated with an increased risk of cardiovascular disease, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, cancer, and neurocognitive impairment. This review summarizes the current evidence on the microbiology-oriented mechanisms that sustain this state. We first outline a multifactorial network in which incomplete repair of intestinal mucosal damage, dysbiosis, reduced short-chain fatty acid production, and disturbed bile acid metabolism generate a patchy "leaky gut." Continuous translocation of bacterial lipopolysaccharide, fungal β-D-glucan, and other microbial products activates monocyte-macrophage and portal-liver inflammatory circuits. These inputs interact with intermittent HIV antigen expression from latent reservoirs, inflammatory cell death, chronic coinfections, lymphoid tissue fibrosis, mitochondrial dysfunction, and traditional lifestyle-related risk factors. Together, they establish a self-reinforcing gut-liver-immune axis that maintains low-grade inflammation and a procoagulant milieu under viral suppression. We then link these mechanisms to organ-specific complications and review the intervention data, focusing on early ART initiation, statin therapy, and cotrimoxazole prophylaxis as a proof-of-concept that modifying inflammatory and mucosal pressures can improve outcomes. Finally, we highlight research priorities and argue that the effective prevention of long-term complications in virally suppressed PLWH requires combination strategies targeting multiple nodes of this network, with particular attention to gut barrier repair and microbiome modulation.