Pathological Proliferation of CD4⁺ T Cells in Late Presentation of HIV Infection After Antiretroviral Therapy

BACKGROUND: Despite the global success of antiretroviral therapy (ART) in reducing human immunodeficiency virus (HIV) related morbidity and mortality, late presentation of HIV infection remains a major challenge. This study aims to explore whether the immune dysregulation of pathological proliferation exists in late presenters (LP). METHODS: People living with HIV (PLWH) were recruited and divided into LP group (n=55, defined as the presence of an AIDS-defining event and/or CD4 count <350 cells/μL) and non-late-presenters (n-LP) group (n=54). We evaluated the phenotype and function of CD4⁺ T cells in PLWH, and their correlation with clinical parameters. Mass cytometry was used to detect and analyze the phenotypic and functional characteristics of CD4⁺ T cells following ART. RESULTS: The LP exhibited significantly lower CD4⁺ T cell counts compared to n-LP. A higher proportion of CD4⁺ T cell subpopulations with characteristics of proliferation (Ki67), activation (HLA-DR), exhaustion (PD-1) and senescence (CD57) was observed in LP. Besides, the proportion of CD4⁺ T cells with "pathological proliferation" properties (such as Ki67⁺CD57⁺, Ki67⁺HLA-DR⁺, Ki67⁺CD38⁺) in LP was much higher than that in n-LP. We found that the immune dysregulation characterized by pathological proliferation is related to multiple clinical parameters in LP. CONCLUSION: LP have persistent immune dysfunction post-ART, characterized by excessive and pathological T cell proliferation accompanied by activation or senescence. Future studies focusing on this pathological proliferation phenomenon will be essential to improve immune recovery, long-term prognosis, and health outcomes in advanced patients.