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Pathogenic simian/human immunodeficiency virus SHIV(KU) inoculated into immunized macaques caused infection, but
P S Silverstein1, G A Mackay, S Mukherjee
1Marion Merrell Dow Laboratory of Viral Pathogenesis, Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Abstract:
Using the simian immunodeficiency virus/human immunodeficiency virus (SHIV)-macaque model of AIDS, we had shown in a previous report that a live, nonpathogenic strain of SHIV, further attenuated by deletion of the vpu gene and inoculated orally into adult macaques, had effectively prevented AIDS following vaginal inoculation with pathogenic SHIV(KU). Examination of lymph nodes from the animals at 18 weeks postchallenge had shown that all six animals were persistently infected with challenge virus. We report here on a 2-year follow-up study on the nature of the persistent infections in these animals. DNA of the vaccine virus was present in the lymph nodes at all time points tested, as far as 135 weeks postchallenge. In contrast, the DNA of SHIV(KU) became undetectable in one animal by week 55 and in three others by week 63. These four macaques have remained negative for SHIV(KU) DNA as far as the last time point examined at week 135. Quantification of the total viral DNA concentration in lymph nodes during the observation period showed a steady decline. All animals developed neutralizing antibody and cytotoxic-T-lymphocyte responses to SHIV(KU) that persisted throughout the observation period. Vaccine-like viruses were isolated from two animals, and a SHIV(KU)-like virus was isolated from one of the two macaques that remained positive for SHIV(KU) DNA. There was no evidence of recombination between the vaccine and the challenge viruses. Thus, immunization with the live vaccine not only prevented disease but also contributed to the steady decline in the virus burdens in the animals.
Insights
A live, attenuated simian-human immunodeficiency virus (SHIV) vaccine prevented AIDS in macaques and led to a long-term decline in viral load. The vaccine virus persisted, while pathogenic SHIV DNA became undetectable in most animals over two years.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Previous studies demonstrated that an orally administered, live-attenuated simian-human immunodeficiency virus (SHIV) strain, with a deleted vpu gene, prevented acquired immunodeficiency syndrome (AIDS) in macaques after challenge with pathogenic SHIV(KU).
- Persistent infection with the challenge virus was confirmed in lymph nodes at 18 weeks post-challenge.
Purpose of the Study:
- To investigate the long-term nature of persistent infections in macaques immunized with the live-attenuated SHIV vaccine and challenged with pathogenic SHIV(KU).
- To assess the durability of vaccine-induced protection and its impact on viral load over a 2-year period.
Main Methods:
- Longitudinal monitoring of viral DNA in lymph nodes for up to 135 weeks post-challenge.
- Quantification of total viral DNA concentration.
- Assessment of neutralizing antibody and cytotoxic-T-lymphocyte responses.
- Isolation of vaccine-like and challenge-like viruses.
Main Results:
- Vaccine virus DNA was consistently detected in lymph nodes throughout the 135-week study period.
- Pathogenic SHIV(KU) DNA became undetectable in four out of six macaques by week 63, remaining negative up to week 135.
- A steady decline in total viral DNA concentration was observed in the lymph nodes of all animals.
- All animals developed persistent neutralizing antibody and cytotoxic-T-lymphocyte responses to SHIV(KU).
- No evidence of recombination between the vaccine and challenge viruses was found.
Conclusions:
- The live-attenuated SHIV vaccine not only prevents AIDS but also contributes to a sustained reduction in viral burden.
- The vaccine-induced immune responses are durable and effective in controlling pathogenic SHIV infection in the long term.
- This study highlights the potential of live-attenuated SHIV vaccines for durable protection against AIDS.