A comparative study was undertaken to characterize the very early events that distinguish attenuated and pathogenic simian immunodeficiency virus (SIV) infections. Three rhesus macaques were inoculated with the attenuated SIVmac 251 delta nef virus, and three others with a virus of intermediate phenotype, SIVmac 239 nef stop. They were compared to four macaques inoculated with the pathogenic SIVmac 251 isolate. Lymph nodes (LN) taken between 7 days and 2 months postinoculation were analyzed for SIV expression by in situ hybridization. During acute infection, SIV 21 delta nef infected 1 to 1.5 log10 fewer cells in LN tissue than the pathogenic SIV 251 isolate. The reduction was more marked in the blood, as SIV 251 delta nef infected 2 to 3 log10 fewer PBMC than the isolate and did not yield detectable antigenemia. Morphometric measurements showed that the development of germinal centers (GC) was more rapid in the delta nef infection, which led to a more efficient trapping of viral particles, and could account for antigenemia clearance. The SIV 239 nef stop clone reverted to a nef+ genotype at Week 2, but induced a lower viral burden than a directly pathogenic virus. The kinetics of GC development was rapid, indicating that SIV 239 nef stop induced an immune response similar to that seen in attenuated infection. This study provides evidence that attenuated SIV elicits a more rapid immune response than pathogenic SIV and suggests that an early immunosuppressive episode may facilitate the dissemination of pathogenic SIV.