innate immunity in live-attenuated aids vaccines
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Publication
Journal: Journal of Virology
November/4/2012
Abstract
Immunization with attenuated lentiviruses is the only reliable method of protecting rhesus macaques (RM) from vaginal challenge with pathogenic simian immunodeficiency virus (SIV). CD8(+) lymphocyte depletion prior to SIVmac239 vaginal challenge demonstrated that a modest, Gag-specific CD8(+) T cell response induced by immunization with simian-human immunodeficiency virus 89.6 (SHIV89.6) protects RM. Although CD8(+) T cells are required for protection, there is no anamnestic expansion of SIV-specific CD8(+) T cells in any tissues except the vagina after challenge. Further, SHIV immunization increased the number of viral target cells in the vagina and cervix, suggesting that the ratio of target cells to antiviral CD8(+) T cells was not a determinant of protection. We hypothesized that persistent replication of the attenuated vaccine virus modulates inflammatory responses and limits T cell activation and expansion by inducing immunoregulatory T cell populations. We found that attenuated SHIV infection decreased the number of circulating plasmacytoid dendritic cells, suppressed T cell activation, decreased mRNA levels of proinflammatory mediators, and increased mRNA levels of immunoregulatory molecules. Three days after SIV vaginal challenge, SHIV-immunized RM had significantly more T regulatory cells in the vagina than the unimmunized RM. By day 14 postchallenge, immune activation and inflammation were characteristic of unimmunized RM but were minimal in SHIV-immunized RM. Thus, a modest vaccine-induced CD8(+) T cell response in the context of immunoregulatory suppression of T cell activation may protect against vaginal HIV transmission.
Publication
Journal: Current Opinion in HIV and AIDS
February/23/2014
Abstract
OBJECTIVE
The development of a preventive HIV vaccine remains an unresolved challenge. Animal models that can predict the results of HIV vaccine efficacy trials and identify the immune mechanisms responsible for vaccine protection would be most useful for HIV vaccine development. The purpose of the current review is to critique recent developments in the use of animal models of HIV infection in preclinical studies of AIDS vaccines and to describe how the use of improved animal models can inform the development of an HIV vaccine.
RESULTS
The results of preclinical experiments with candidate HIV vaccines can vary with the SIV challenge virus used. It is now known that there is considerable variability in the neutralization sensitivity and that the level of viral sequence diversity within the challenge stocks varies. This has allowed more realistic preclinical vaccine studies with heterologous vaccine antigens and challenge viruses. Further, the dose of challenge virus and the route of virus challenge can modify the efficacy of candidate vaccines in preclinical studies.
CONCLUSIONS
Recent experiments demonstrate that nonhuman primate models of AIDS can reproduce the complex biology of HIV transmission, recapitulate the results of HIV vaccine efficacy trials in humans and be used to identify correlates of protection.