METTL3-mediated SOCS3 m 6 A Modification in Preserving CD4 + T Cell Homeostasis in HIV Infected Long-term Non-progressors

ABSTRACT The maintenance of normal CD4 + T cell levels in human immunodeficiency virus (HIV) infected long-term non-progressors (LTNPs) remains elusive. N6-methyladenosine (m 6 A) regulates RNA metabolism and immune function, but its role in LTNP pathogenesis is unelucidated. This study integrated in vivo analyses of peripheral blood mononuclear cells (PBMCs) from LTNPs, typical progressors (TPs), ART-treated patients, and healthy controls with in vitro experiments using the MT2-HIV-1 ⅢB model to explored the m 6 A regulatory role in LTNPs. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) identified uniquely elevated m 6 A modification abundance and METTL3 expression in LTNPs vs. TPs. Differential m 6 A and mRNA analysis bighlighted enrichment of innate immunity/inflammation pathways, particularly the SOCS/IL/JAK axis. Further experiments confirmed that METTL3 mediates m 6 A modification of SOCS3, which suppresses JAK2/STAT4 phosphorylation to modulate IL-12/IFN-γ/IL-4 expression. These findings uncover a novel m 6 A-METTL3-SOCS3 regulatory axis underlying HIV long-term non-progression, explaining preserved CD4 + T cell homeostasis in LTNPs. IMPOTANCE LTNPs represent a unique subset of HIV-infected individuals who naturally maintain normal CD4⁺ T cell levels and slow disease progression, offering a valuable model to dissect host protective mechanisms against HIV. m⁶A modification has emerged as a pivotal regulator roles in HIV replication and T cell activation, yet its contribution to LTNP biology has remained unclear. This novel mechanism provides a potential explanation for the maintenance of normal CD4 + T cell levels in LTNPs. Our findings shed light on the molecular basis of HIV-1 long-term non-progression and offered crucial insights for developing functional cure for AIDS and new host immune strategies.