Important note: Information in this article was accurate in July 2000. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, July 12 & 19, 1999
Daniel J. DeNoon, Senior Editor
(CW HENDERSON PUBLISHER (http://www.newsrx.net/) -- A very highly attenuated, live simian immunodeficiency virus (SIV) vaccine protected two of four monkeys against vaginal challenge with pathogenic SIV.
The results are the first good news in a long time for proponents of testing live HIV vaccines. Recently, people naturally infected with a naturally occurring nef-deleted mutant have had declines in CD4 lymphocyte counts after remaining immunologically normal for extended periods (see accompanying story).
The highly attenuated vaccine, SIV[mac239]delta4, lacks its nef, vpr, vpx, and upstream sequences (US) in the U3 region of its genome.
"We are encouraged that a strain as attenuated as SIV[mac239]delta4 can still give reasonable levels of protection against natural exposure to a virulent SIV more than one year after the time of vaccination," wrote R. Paul Johnson and Ronald C. Desrosiers of Harvard Medical School and colleagues.
"It may be possible in future experiments to get protection with even more attenuated strains by the inclusion of specific types of booster immunizations."
Johnson et al. reported their findings in the Journal of Virology ("Highly Attenuated Vaccine Strains of Simian Immunodeficiency Virus Protect against Vaginal Challenge: Inverse Relationship of Degree of Protection with Level of Attenuation," J Virol 1999 Jun;73(6):4952-61.
The researchers tested three live-virus vaccines, each more attenuated than the last: SIV[mac239]delta3 (lacking unique nef, vpr, and nef sequences that overlap the US); SIV[mac239]delta3X (lacking nef, vpx, and US sequences); and SIV[mac239]delta4.
All animals received a single intravenous inoculation; 61 weeks later they were challenged with pathogenic SIVmac251 by vaginal exposure.
Degree of attenuation was clearly related to protection: all four delta3-vaccinated animals were protected, while one of the delta3X- and two of the delta4-vaccinated animals developed superinfection with the challenge virus.
Protection against vaginal challenge was clearly easier to achieve than protection against intravenous challenge: despite far lower challenge doses, four additional delta4-vaccinated monkeys all became infected after intravenous challenge.
Although the vaccinated animals that became superinfected with challenge virus had lower-level infections than unvaccinated control animals, previous experience suggests that they will develop AIDS but at a slower rate.
The small numbers of animals in the present study did not allow definitive identification of exactly which immune responses were protective. However, neutralizing antibodies apparently played no role.
"Protection against vaginal challenge in the delta4-vaccinated group occurred in the absence of detectable serum neutralizing activities and appeared to be associated with the development of an early SIV specific cytotoxic lymphocyte (CTL) response," Johnson et al. observed.
"Further analysis of larger cohorts of animals vaccinated with highly attenuated SIV strains, coupled with more quantitative assessments of cellular immune responses, such as those derived from the use of major histocompatibility complex tetramers, should allow more detailed evidence for immune correlates of protection by live, attenuated SIV."
This work was supported by Public Health Service grants and with federal funds from the National Cancer Institute, National Institutes of Health.
The corresponding author for this study is Ronald C. Desrosiers, New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Dr., P.O. Box 9102, Southborough, Massachusetts 01772-9102. Phone: (508) 624-8042. Fax: (508) 624-8190. Email: <ronald_desrosiers@hms.harvard.edu>.
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