Abnormal characteristics of intestinal microenvironment in HIV immunological non-responders

Acquired immunodeficiency syndrome (AIDS) is one of the most dangerous diseases threatening global public health. Antiretroviral therapy (ART) is currently the primary treatment for people living with HIV (PLWH). However, some patients are classified as immunological non-responders (INRs), defined by the failure to achieve adequate CD4⁺ T cells reconstitution despite continuous viral suppression, and are associated with inferior clinical outcomes. This behavior may be linked to the ongoing dysfunction of the intestinal microenvironment. Although PLWH exhibit similar clinical changes such as intestinal mucosal injury, barrier failure, and microbial community problems, intestinal microenvironment abnormalities in INRs are more severe. The specific manifestations include persistently low levels of intestinal CD4⁺ T cells with limited reconstitution, along with a significant reduction in the proportion of Th17 cells, leading to severe impairment of mucosal anti-infective capacity and immune regulatory function. Additionally, elevated levels of pro-inflammatory mediators drive chronic inflammation, thereby exacerbating tissue damage. Furthermore, microbial dysbiosis is more pronounced, characterized by a marked decrease in beneficial symbiotic bacteria and an expansion of opportunistic pathogens. In contrast, immunological responders showed some degree of recovery in these indicators. These pathological features are not only associated with a higher risk of disease progression and complications in INRs but also provide a theoretical basis for developing adjuvant treatment strategies targeting intestinal immune reconstitution. In addition, we summarize the current mainstream definitions of INRs and propose a more robust definition. This review systematically elaborates the pathogenic mechanisms and potential intervention strategies underlying intestinal microenvironment abnormalities in INRs and holds important clinical value for improving the long-term prognosis of patients and advancing individualized treatment.