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Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation
Regina Hofmann-Lehmann1, Josef Vlasak, Alison L Williams
1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
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.
Conclusion:
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.
Insights
A live attenuated SIV vaccine, SIVmac239Delta3, caused immune dysregulation and AIDS in most adult monkeys years after vaccination. This suggests caution for live attenuated HIV vaccines in humans.
Area of Science:
- Veterinary Immunology
- Virology
- Vaccinology
Background:
- A live attenuated simian-immunodeficiency virus (SIV) vaccine, SIVmac239Delta3, with large deletions, was previously associated with AIDS in infant-vaccinated monkeys.
- The pathogenic potential of this vaccine in adult animals remained less understood.
Purpose of the Study:
- To investigate the long-term pathogenicity of the live attenuated SIVmac239Delta3 vaccine in adult rhesus macaques.
- To assess the development of immune dysregulation and AIDS-like pathology following adult vaccination.
Main Methods:
- Eleven adult rhesus macaques were vaccinated with SIVmac239Delta3.
- Vaccinees were monitored for extended periods (up to 6.8 years) for clinical signs and immunological parameters.
Main Results:
- All 11 adult vaccinees exhibited immune dysregulation, including inverted CD4:CD8 T-cell ratios and recurrent viremia.
- Six vaccinees (55%) developed decreased CD4 T-cell counts, and two (18%) progressed to AIDS.
- Poor prognostic signs included chronic, recurrent viremia and cytoviremia.
Conclusions:
- The live attenuated SIVmac239Delta3 vaccine can induce significant immune dysregulation and AIDS in adult macaques over time.
- Pathogenic effects manifested several years post-vaccination, highlighting the importance of long-term follow-up.
- The findings contraindicate mass vaccination of humans with similar live attenuated HIV vaccines due to potential long-term risks.