The cytopathicity of a simian immunodeficiency virus Mne variant is determined by mutations in Gag and Env.
Previous studies suggested that the rapidly replicating, highly cytopathic, syncytium-inducing (rapid-high/SI) phenotype of simian immunodeficiency virus Mne variants that evolved in macaques inoculated with a slowly replicating, minimally cytopathic, non-syncytium-inducing (slow-low/NSI) molecular clone was not solely the result of changes in the envelope surface protein (Env SU). To define the viral determinants responsible for the change in phenotype, we molecularly cloned a rapid-high/SI variant (designated SIVMne170) derived from the peripheral blood mononuclear cells (PBMCs) of a pig-tailed macaque that was inoculated with a slow-low/NSI molecular clone, SIVMneCL8. SIVMne170 was SI and replicated with faster kinetics and was more cytopathic than the parent SIVMneCL8 in CEMx174 cells. Additionally, SIVMne170 was more cytopathic for the CD4+ T-cell population than SIVMneCL8 in macaque PBMCs. An analysis of chimeric viruses constructed between the variant SIVMne170 and the parent virus SIVMneCL8 demonstrated that there are determinants encoded within both the 5' and 3' halves of SIVMne170 that independently contribute to its rapid-high/SI phenotype. As we previously observed with other SIVMne variants, the Env SU of SIVMne170 was important for syncytium induction but was not a key determinant of cytopathicity. By contrast, the intracellular domain of the envelope transmembrane protein (Env TM) contributed to both the SI and cytopathic properties of SIVMne170. We also found that the minimal determinant within the 5' half of SIVMne170 that conferred its rapid replication kinetics and cytopathicity mapped to the capsid- and nucleocapsid-encoding regions of gag. Together, these data demonstrate that mutations selected in Gag and Env TM intracytoplasmic tail influence the replication and cytopathicity of SIVMne variants that evolve in the host.
Kimata
J T
JT
Department of Microbiology, University of Washington, Seattle 98195, USA.
Overbaugh
J
J
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D002678:Chimera; D003001:Cloning, Molecular; D017931:DNA Primers; D015686:Gene Products, env / Q000096:biosynthesis / Q000737:chemistry; D015683:Gene Products, gag / Q000096:biosynthesis / Q000737:chemistry; D015752:Genes, env; D015750:Genes, gag; D014644:Genetic Variation; D015726:Giant Cells; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008214:Lymphocytes / Q000821:virology; D008254:Macaca nemestrina; D008264:Macrophages / Q000821:virology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000821:virology; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017931:DNA Primers; D015686:Gene Products, env; D015683:Gene Products, gag