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Live attenuated lentiviruses are potentially effective candidate HIV vaccines; however, delivery of these viruses in the field would be problematic. Delivery of attenuated lentiviruses as proviral DNA would be a simple means of immunization, but the efficiency of this method of delivery is not known. In this study, macaques were readily infected following inoculation of plasmid DNA encoding proviral simian immunodeficiency virus (SIVmac239), whether given i.m. (300 microg) or epidermally (15 microg), with all four animals succumbing to AIDS at a mean of 26 weeks following inoculation. Using a human skin explant model, we found that the 50% infectious dose (ID50) of proviral SIV or HIV-1 plasmid may be as low as 1 microg when delivered to skin by gold particle bombardment using a gene gun. An infectious proviral clone of SIV mac239 with a 105 bp deletion in the 3' nef/LTR overlap region was engineered (SIVsbbc delta3), analogous to the initial common nef/LTR deletion in HIV-1 strains isolated from an Australian cohort of long-term slow-progressors. Two further macaques were also readily infected with SIVsbbc delta3 after i.m. injection of 300 microg of highly purified plasmid DNA. Unexpectedly, in one macaque inoculated with SIVsbbc delta3 DNA, SIV strains isolated three to six weeks after infection had completely repaired the nef/LTR deletion with wild-type sequence, and eventually progressed to AIDS. The mechanism used to rebuild this deletion with wild-type sequence, presumably derived from an intact 5' LTR, is unclear, but possibilities include RNA read-through errors from the plasmid DNA and recombination with residual plasmid DNA at the inoculation site.