Since Vpu, Env, and Nef are expressed in a stage-specific manner of the HIV-1 life cycle—that is, Nef is expressed at early stages, while Env and Vpu are encoded from messages harboring Rev-responsive element (RRE) and thus at late stages of the HIV-1 life cycle—intracellular-expressed Nef at the early infection downregulate CD4 by enhancing its internalization and directing the receptor to lysosomes for degradation [20,75,76,77,78,79]. The gene discussed is ERVW-1; the disease is infection.