Molecular changes in Nef with progression to AIDS. We have compared nef gene sequences isolated by polymerase chain reaction from peripheral blood lymphocyte DNA of macaques which had been inoculated with either biologically (E11S) or molecularly cloned SIV/Mne (clone 8). Two samples from each animal obtained early (wk 2-8) or late (wk 21-137) after infection were analyzed. Four substitutions in the predicted Nef amino acid sequence were seen in all animals at the late time point, and a fifth in all but one. Two of the common exchanges are located about 40 residues apart in the Nef core sequence, but are in proximity on the tertiary structure as judged by computer modeling using the structure of the HIV Nef core protein as a guide. Most recurring in vivo changes replaced a residue found in the cloned Nef sequence with one present in a consensus derived by aligning the Nef sequences of the SIV/Sm clade. Animals inoculated with virus already containing the late version nef gene developed a more aggressive disease. Recombinant virus containing a macaque adapted nef (MA-nef) on the clone 8 backbone was threefold more infectious on SMAGI cells than the original virus. A lymphocyte line infected with SIV-clone8MA-nef contained a large proportion of cells carrying proviruses with defective nef genes. These findings suggest that the nef gene of the cloned SIV/Mne had undergone attenuating mutations during propagation in tissue culture which were corrected in vivo. Chimeric viruses containing the late nef gene sequence associated with AIDS will be tested for pathogenicity in macaques in vivo. Nef and progression to AIDS - AIDS, antiviral, baboons, foamy retrovirus, macaques, simian immunodeficiency virus, - Human Tissues, Fluids, Cells, etc.