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Published on: November 1, 2011
Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14
S Dewhurst1, J E Embretson, D C Anderson
1Harvard University, School of Public Health, Boston, Massachusetts 02115.
Abstract:
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.
Insights
Simian immunodeficiency virus (SIVSMM-PBj14) causes rapid, fatal disease in macaques. Molecular cloning identified infectious viral components responsible for this acute pathogenicity, offering insights into lentivirus virulence.
Area of Science:
- Virology
- Immunology
- Primate Lentiviruses
Background:
- Simian immunodeficiency virus from sooty mangabey monkeys (SIVSMM-PBj14) is a highly pathogenic primate lentivirus.
- It consistently causes fatal disease in pig-tailed macaques within 8 days.
Purpose of the Study:
- To identify viral genes and products influencing the acute pathogenicity of SIVSMM-PBj14.
- To molecularly define the infectious components of this virulent lentivirus.
Main Methods:
- Polymerase chain reaction amplification of the SIVSMM-PBj14 genome into 5' and 3' halves.
- Molecular cloning of amplified viral DNA.
- DNA sequence analysis and inoculation of pig-tailed macaques with cloned viral halves.
Main Results:
- Sequence analysis revealed conservation with other SIVs, except for a duplication in the long terminal repeat enhancer region, creating an additional NF-kappa B binding site.
- Four of six examined genomic halves produced infectious virus.
- Infectious virus induced acute disease and death in macaques within 6 days, mirroring the uncloned isolate's effects.
- Molecularly cloned viruses exhibited cytopathicity for mangabey CD4+ cells.
Conclusions:
- This study presents the first instance of acute immunodeficiency disease induced by a molecularly defined lentivirus.
- The findings suggest that specific molecularly defined components of SIVSMM-PBj14 are responsible for its high pathogenicity.
- Cytopathicity for CD4+ cells may correlate with the in vivo pathogenicity observed.
