Identification and biologic characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM)

Abstract

A virus pool isolated from lymphoid tissue of a macaque (PBj) infected for 14 months with SIV/SMM was found to be associated with acute disease and death. Six of six pig-tailed macaques, one of three rhesus macaques, and three of four SIV/SMM-seronegative mangabeys developed acute disease within 5 days and died from 7 to 13 days postinoculation; however, neither of two SIV/SMM-infected mangabeys died or developed disease. The virus associated with acute disease and death was shown by electron microscopy to be a lentivirus and was serologically indistinguishable from SIV/SMM by immunofluorescence and radioimmunoprecipitation assays. A biologic clone generated from lymphoid tissue of an animal that died 7 days after inoculation of the lethal pool resulted in death within 8 days of three of three pig-tailed macaques. Comparison of the lethal virus, designated SIV/SMM(PBj14), with the parent virus, SIV/SMM-9 (the isolate with which macaque PBj was originally inoculated), showed that although the kinetics of replication in peripheral blood mononuclear cells (PBMC) from pig-tailed macaques and mangabey monkeys were similar, SIV/SMM(PBj14) replicated more efficiently than SIV/SMM-9 in human PBMC and also replicated in chimpanzee PBMC whereas SIV/SMM and other SIV isolates did not. In addition, the variant was shown to replicate efficiently in some established cell lines whereas replication of SIV/SMM-9 in cell lines could be demonstrated only occasionally. That parental SIV/SMM-9, but not SIV/SMM(PBj14), was neutralized by serum from macaque PBj suggests that the variant may have been generated by immune selection. Comparison of sequential virus isolates from macaque PBj for host range and the ability to be neutralized and of sequential serum samples for neutralization activity indicated that changes in biologic properties were detected in virus isolates and serum obtained at 6 months after infection and later. Normal macaque PBMC infected in vitro with SIV/SMM(PBj14), but not with SIV/SMM-9 or other virus pools from PBj, formed syncytia with Sup-T1 cells, whereas all isolates formed syncytia with MOLT-4 clone 8 cells. These data suggest that, relative to SIV/SMM-9, SIV/SMM(PBj14) acquired multiple mutations, at least one (or more) of which is in the gene coding for the envelope glycoprotein. Continued analysis of this series of SIV/SMM isolates with diverse properties may lead to the identification of specific regions of the viral genome that influence defined biologic properties. Furthermore, the availability of a strain of SIV that induces rapid onset of disease and death may facilitate screening of drugs for antiviral activity against lentiviruses.