title: Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation.
abstract: OBJECTIVE
  A live attenuated SIV vaccine strain, termed SIVmac239Delta3 and containing large deletions in, and the negative regulatory element, was previously shown to cause AIDS mostly in monkeys vaccinated as infants. In the present study, we demonstrate that SIVmac239Delta3 is pathogenic in most vaccinated adult monkeys, given enough time.
  
  
  METHODS
  Eleven rhesus macaques vaccinated as adults with SIVmac239Delta3 were followed for extended periods (up to 6.8 years).
  
  
  RESULTS
  We found signs of immune dysregulation in all 11 adult vaccinees. All animals developed persistently inverted CD4 : CD8 T-cell ratios, seven (64%) had persistent recurrent viremia, and six (55%) had decreased CD4 T-cell counts (< 500 x 10 cells/l). Further signs included low CD4CD29 lymphocyte subsets, loss of anti-Gag antibodies, anemia, thrombocytopenia, wasting, and opportunistic infections. Two adult vaccinees (18%) subsequently developed AIDS. Development of chronic, recurrent viremia with plasma viral RNA loads > or = 10 copies/ml and cytoviremia was a poor prognostic sign.
  
  
  CONCLUSIONS
  Our data demonstrate that with time, a live attenuated, multiply deleted SIV vaccine can cause immune dysregulation in most vaccine recipients, even in initially immune competent, healthy adults. Immune dysfunction can progress to full AIDS. However, pathogenic effects became evident only several years after vaccination. Thus, mass vaccination of humans with similarly constructed live attenuated HIV vaccines, recently suggested for countries with high HIV-1 transmission rates, seems contraindicated.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Hofmann-Lehmann
authors.forename: Josef
authors.initials: J
authors.lastname: Vlasak
authors.forename: Alison L
authors.initials: AL
authors.lastname: Williams
authors.forename: Agnès-Laurence
authors.initials: AL
authors.lastname: Chenine
authors.forename: Harold M
authors.initials: HM
authors.lastname: McClure
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anderson
authors.forename: Shawn
authors.initials: S
authors.lastname: O'Neil
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D017353:Gene Deletion; D015686:Gene Products, env / Q000235:genetics; D015754:Genes, nef; D008253:Macaca mulatta; D011379:Prognosis; D012008:Recurrence; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D018449:SAIDS Vaccines / Q000009:adverse effects*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000209:etiology* / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D014613:Vaccines, Attenuated / Q000009:adverse effects; D014760:Viral Fusion Proteins / Q000235:genetics; D014766:Viremia / Q000209:etiology
chemical_list: D015686:Gene Products, env; D015682:Retroviridae Proteins, Oncogenic; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D014760:Viral Fusion Proteins; C059580:transmembrane protein, Simian immunodeficiency virus