Plasma from macaques inoculated with macrophage-tropic SIVmac were tested for neutralization/enhancement of macrophage-tropic SIVmac239-17EBR in normal rhesus macrophages. The plasma of a macaque (R71) that developed a highly virulent neuro-tropic (macrophage-tropic) strain of SIVmac in neuro-adaptation studies significantly enhanced infection of SIVmac239-17EBR as well as infection of dual-tropic SIVmac251. Plasma from other macaques that were inoculated with macrophage-tropic virus, neutralized SIVmac239-17EBR. Also, plasma from macaques infected with lymphocyte-tropic SIVmac239 or dual-tropic SIVmac251 neutralized SIVmac251 infection. When the effect of R71 plasma on the early stages of the SIV life cycle was investigated, this plasma significantly increased binding of 35S-methionine labeled SIVmac239-17EBR and increased binding of 35S-SIVmac251 to primary macrophages, unlike plasma from other macaques infected with either macrophage-tropic or lymphocyte-tropic SIV. A single-cycle infection assay showed higher percentages of positive cells and more intense fluorescence in cultures treated with R71 plasma compared with control plasma. By in situ hybridization, SIV RNA transcripts were detected earlier (12 hr post-infection) and in higher percentages, in cultures treated with R71 plasma than in cultures treated with control plasma (18 hr post-infection). These results indicate that enhancing activity in infected macaque plasma may be associated with severe infection by highly virulent macrophage-tropic (neuro-tropic) SIV. The enhancing effect occurs early in infection and results in increased transcription of SIV RNA.