Surface modifications can endow nanomaterials with presupposed immunoregulatory functions to optimize vaccine-induced immune responses. In this work, we modified an immunoregulatory molecule, amantadine (Ada), on the outermost layer of PVP-PEG-coated silver nanorods (Ada-PVP-PEG silver nanorods). Such Ada surface-modified silver nanorods promote HIV vaccine-triggered cytotoxic lymphocytes (CTLs) to produce around eightfold stronger tumor necrosis factor alpha (TNF-α) in vivo. The enhancement of HIV-specific CTL-derived TNF-α significantly facilitates the death of HIV-infected cells (from 28.86 to 84.19%) and reduces HIV production (around sixfold). This work supports the critical role of surface modifications of nanomaterials in fundamentally improving the immunotherapy of HIV vaccine against HIV-infected cells.