Induction of AIDS in rhesus monkeys by a recombinant simian immunodeficiency virus expressing nef of human immunodeficiency virus type 1.
A nef gene is present in all primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus of macaque monkeys (SIVmac). However, the nef genes of HIV-1 and SIVmac exhibit minimal sequence identity, and not all properties are shared by the two. Nef sequences of SIVmac239 were replaced by four independent nef alleles of HIV-1 in a context that was optimal for expression. The sources of the HIV-1 nef sequences included NL 4-3, a variant NL 4-3 gene derived from a recombinant-infected rhesus monkey, a patient nef allele, and a nef consensus sequence. Of 16 rhesus monkeys infected with these SHIVnef chimeras, 9 maintained high viral loads for prolonged periods, as observed with the parental SIVmac239, and 6 have died with AIDS 52 to 110 weeks postinfection. Persistent high loads were observed at similar frequencies with the four different SIV recombinants that expressed these independent HIV-1 nef alleles. Infection with other recombinant SHIVnef constructions resulted in sequence changes in infected monkeys that either created an open nef reading frame or optimized the HIV-1 nef translational context. The HIV-1 nef gene was uniformly retained in all SHIVnef-infected monkeys. These results demonstrate that HIV-1 nef can substitute for SIVmac nef in vivo to produce a pathogenic infection. However, the model suffers from an inability to consistently obtain persisting high viral loads in 100% of the infected animals, as is observed with the parental SIVmac239.
Alexander
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New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772-9102, USA.
Du
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Howe
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Czajak
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Desrosiers
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RC
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004279:DNA, Viral; D015870:Gene Expression; D015693:Gene Products, nef / Q000235:genetics / Q000502:physiology*; D015497:HIV-1; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D015302:Simian Immunodeficiency Virus / Q000254:growth & development / Q000502:physiology*; D054311:nef Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus