Rev-independent simian immunodeficiency virus strains are nonpathogenic inneonatal macaques

The viral protein Rev is essential for the export of the subset of unsplice d and partially spliced lentiviral mRNAs and the production of structural p roteins. Rev and its RNA binding site RRE can be replaced in both human imm unodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the co nstitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogen icity of a pair of SIV mutant strains generated from Rev-independent molecu lar clones of SIVmac239 which differ only in the presence of the nef open r eading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfun ction or disease during follow-up ranging from 2.3 to 4 years. Therefore, t he Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. These data demonstrate that Rev regulation plays an important role in the p athogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel app roach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a part ial block of Rev function may modulate disease progression in HIV-infected individuals.