The HIV-1 Nef Protein: How An AIDS Pathogenetic Factor Turns to a Tool for Combating AIDS

Nef is one of the six regulatory proteins coded by the Human Immunodeficiency Virus (HIV)-1 and -2, and by the Simian Immunodeficiency Virus (SIV). Accumulating experimental evidences indicate that Nef is required for the optimal infectivity of HIV viral particles, and that it plays a critical role in the AIDS pathogenesis progressing. We previously cloned and sequenced a functionally defective HIV-1 genome (F12HIV-1) whose nef gene showed a rather unusual feature, i.e. its expression blocks the HIV-1 release by interfering with the viral assembling / release. Such a striking phenotype appeared to be the result of three amino acid substitutions, and coupled with the loss of the most part of the Nef functions described for the wild type counterpart. The F12Nef properties encouraged the designing of new strategies of anti HIV-1 gene therapy we afforded by recovering an inducible lentivirus vector expressing F12Nef as the cytoplasmic domain of a transmembrane fusion protein including a selectable marker (i.e. the Nerve Growth Factor receptor) as the ecto- and transmembrane domains. As expected, the expression of such a chimeric protein resulted in a potent protection of transduced cells from the HIV-1 spread. In sum, and surprisingly enough, we generated a reagent effectively counteracting the HIV-1 replication through the combination of a slightly mutated AIDS pathogenetic factor together with a lentivirus vector, i.e. the result of artifactual modifications of the HIV-1 genome.