The present invention relates to antibody derivatives against HIV based on a mutated CD4-IgG scaffold with enhanced antiviral and immunomodulatory activities. These antibody derivatives are characterized for having an increased ability to (i) block the entry of human immunodeficiency virus (HIV) into host cells and (ii) elicit effector functions through the activation, of natural killer (NK) cells. The present invention further relates to nucleic acids, vectors and host cells expressing said antibody derivatives, as well their therapeutic and diagnostic applications in human health.