Suboptimal nucleotides in the infectious, pathogenic simian immunodeficiency virus clone SIVmac239.
We analyzed virus sequences in two monkeys infected with SIVmac239 and two monkeys infected with SHIVnef that maintained high, persisting viral loads. Sequence changes were observed consistently at four loci in all four animals: a single nucleotide change in the Lys-tRNA primer binding site in the 5' long terminal repeat; two nucleotide changes that resulted in two amino acid changes in the pol gene product; and a single nucleotide change in the region of the simian immunodeficiency virus genome where the rev and env genes overlap, resulting in changes in the predicted amino acid sequences of both gene products. None of these mutations were seen in short-term cultures of CEMx174 cells infected with SIVmac239 or SHIVnef. At all four positions in all four animals, the new sequences represented consensus sequences for primate lentiviruses, whereas the inoculum sequences at these four loci have either never been or rarely been reported outside of SIVmac239. Thus, although cloned SIVmac239 is consistently pathogenic and consistently induces high viral load set points, it is clearly less than optimal at these four nucleotide positions.
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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Alexander
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Denekamp
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Czajak
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Desrosiers
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016384:Consensus Sequence / Q000235:genetics; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000737:chemistry / Q000235:genetics; D015693:Gene Products, nef / Q000502:physiology; D015684:Gene Products, pol / Q000737:chemistry / Q000235:genetics; D015694:Gene Products, rev / Q000737:chemistry / Q000235:genetics; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D008253:Macaca mulatta / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012357:RNA, Transfer, Lys / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D020079:Terminal Repeat Sequences / Q000235:genetics; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
D015686:Gene Products, env; D015693:Gene Products, nef; D015684:Gene Products, pol; D015694:Gene Products, rev; D015696:Gene Products, tat; D012357:RNA, Transfer, Lys; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus