The clinical and immunological paradox of antiretroviral therapy-induced autoimmunity: the intersecting roles of the Th17/Treg Axis, HLA susceptibility, and accelerated telomeric senescence.

Antiretroviral therapy (ART) has shifted HIV-1 infection into a manageable chronic condition. However, immune reconstitution is occasionally complicated by the de novo emergence of autoimmune diseases (AiDs), presenting a profound immunological paradox. This review evaluates the molecular, phase-specific pathogenetic sequence driving ART-induced autoimmunity at the intersection of cytokine networks, host genetics, and nuclear senescence. A systematic literature search (1985-2026) was conducted across PubMed, Embase, and Scopus using high-density Boolean strings targeting HIV, AiDs, immune reconstitution inflammatory syndrome, cytokines, and telomeric metrics. Results indicate that immune repopulation occurs in distinct phases matching memory and naive T-cell waves. Host immunogenetics heavily regulate susceptibility; mathematical derivation yields a Relative Risk (RR) ratio of 1.12 for individuals lacking the protective HLA-DRB1*13 allele. Chronic retroviral stress and high reactive oxygen species accelerate telomeric erosion. Critically shortened telomeres are associated with a DNA damage response, which may promote an immune cell transition into a Senescence-Associated Secretory Phenotype (SASP) marked by elevated Interleukin-6 (IL-6) secretion. Elevated IL-6 signaling is linked to altered peripheral tolerance, potentially shifting the Th17/Treg axis toward pathogenic Th17 cell differentiation. Post-ART autoimmunity is associated with accelerated immunosenescence, Th17/Treg imbalances, and hypothesized post-transcriptional controls governed by the Arid5a/Regnase-1 balance over IL-6 transcripts.