To manage these hard-to-diagnose cases, the guidelines suggest that LP should be performed in all PLWH asymptomatic for neurological signs/symptoms with late syphilis and CD4+ cells ≤ 350/mm3 and/or a serum Venereal Disease Research Laboratory/Rapid Plasma Reagin (VDRL/RPR) title > 1:32 in the case of “serological failure” after syphilis therapy or the use of alternative treatment during late syphilis [7]. The gene discussed is CD4; the disease is syphilis.