Together, our study suggests that the development of neutralizing antibodies during chronic HIV infection is multifactorial, and associated with i) a CD4 T cell programing favoring the differentiation towards TFH cells, especially ones with increased stemness and long-lived capacity and decreased prevalence of a Th1-like TFH phenotype, ii) a B cell programing enabling the formation of anatomical DZ and DZ GC B cells, iii) reduced GC suppressive activity and iv) higher evolution of Env. The gene discussed is CD4; the disease is HIV infectious disease.