THE TYROSINE-17 RESIDUE OF NEF IN SIVSMMPBJ14 IS REQUIRED FOR ACUTE PATHOGENESIS AND CONTRIBUTES TO REPLICATION IN MACROPHAGES

The variant simian immunodeficiency Virus termed SIVsmmPBj14 induces a rapidly fatal disease in pig-tailed macaques. The acute pathogenic ef fects of this virus appear to be associated with at least two in vitro characteristics: the ability to induce lymphocyte proliferation; and the ability to replicate in unstimulated PBMC. Two of the amino acids in Nef of PBj14 (the No. 17 residue, tyrosine, and the Mo. 18 residue, glutamic acid) appear to be linked to the virus' ability to induce ly mphocyte activation. To further study the effects of these amino acids on PBj14-induced pathogenesis, we generated two mutant viruses from o ur molecular clone, PBj6.6, containing either changes in both the No. 17 and No. 18 residues (termed PBj6.6YE-RQ), or a single change in the No. 17 residue (termed PBj6.6Y-R). In vitro analyses of these viruses showed that while their replicative abilities in stimulated periphera l blood mononuclear cells (PBMC) were altered, they still maintained t he ability to replicate in unstimulated PBMC. Replication of these Vir uses in macrophage populations was impaired relative to the wild-type virus. Both mutant viruses were unable to induce proliferation of maca que PBMC in vitro. Virus derived from PBj6.6Y-R was unable to induce a cute disease in macaques, but did maintain the ability to induce lymph openia and intestinal lymphoid hyperplasia. These results show that th e tyrosine-17 residue of Nef is linked to lymphocyte proliferation and disease development, but also suggest that the pathogenic characteris tics of SIVsmmPBj14 are dependent upon multiple genetic determinants. (C) 1998 Academic Press.