Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14.
The PBj14 isolate of simian immunodeficiency virus from sooty mangabey monkeys (SIVSMM-PBj14) is the most acutely pathogenic primate lentivirus so far described, always causing fatal disease in pig-tailed macaques (Macaca nemestrina) within 8 days of inoculation. As a first step in identifying viral genes and gene products that influence pathogenicity, the SIVSMM-PBj14 genome was amplified by the polymerase chain reaction as 5' and 3' genomic halves of 5.1 and 5.8 kilobases, respectively, and molecularly cloned. DNA sequence analysis revealed a high degree of conservation with other SIVs, except for a 22-base-pair duplication in the enhancer region of the viral long terminal repeat which included a second binding site for the transcription factor NF-kappa B. Of six genomic halves examined, four contributed to the formation of infectious virus that induced acute disease and death in pig-tailed macaques as early as 6 days post-inoculation, with pathology, disease syndromes and kinetics indistinguishable from those induced by the uncloned isolate. To our knowledge this is the first example of acute immunodeficiency disease induced by a molecularly defined lentivirus. Furthermore, the molecularly cloned SIVSMM-PBj14 viruses share with the uncloned virus cytopathicity for mangabey CD4+ cells, a property that may correlate with their observed pathogenicity in vivo.
Dewhurst
S
S
Harvard University, School of Public Health, Boston, Massachusetts 02115.
Embretson
J E
JE
Anderson
D C
DC
Mullins
J I
JI
Fultz
P N
PN
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002520:Cercopithecidae; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology; D004742:Enhancer Elements, Genetic; D005814:Genes, Viral; D007958:Leukocyte Count; D008253:Macaca mulatta; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D016328:NF-kappa B; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D012192:Retroviridae Infections / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology; D012689:Sequence Homology, Nucleic Acid; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity; D013045:Species Specificity; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D004279:DNA, Viral; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014157:Transcription Factors