Background:  Central memory T cells have higher levels of survival signals. In contrast, effector T cells, which do not proliferate or provide immunological memory, have high levels of pro-apoptotic signals. Furthermore, polyfunctional T-cell responses are associated with control of virus replication during chronic HIV infection. The purpose of the present study was to determine if the nature of specific T-cell responses distinguish between protected and unprotected animals in a live-attenuated lentivirus model.

Methods:  MHC class I haplotypes and Gag-epitope specific T-cell responses of 4 simian/human immunodeficiency virus (SHIV)_89.6-vaccinated and simian immunodeficiency virus (SIV)_mac239-challenged rhesus macaques (2 protected and 2 unprotected) were defined using a matrix of peptides in an interferon-gamma (IFN-g) ELISpot assay. Frozen cells were used for peptide-specific stimulation in flow cytometry assays using 2 different 8-color panels that included:  survival vs pro-apoptotic signals (Bcl-2, Caspase-3, 7-AAD); and intracelullar cytokines and degranulation marker (IFN-g, tumor necrosis factor-alpha [TNF-a], interleukin-2 [IL-2], CD107). In addition, T-cell phenotype was assessed.

Results:  T cells from the vaccinated-protected animals had a higher ratio of survival signals (Bcl-2) vs death signals (cleaved caspase-3) when stimulated with the specific SIV peptide; and plasma vRNA levels correlated with the Bcl-2/caspase-3 ratio in SIV-specific T cells. In addition, polyfunctional SIV-specific CD8⁺ T-cell responses were found in the protected animals. Furthermore, although the overall strength of T-cell responses was similar, a decline in frequency of SIV-Gag specific naive and central memory and an increase in the frequency of effector memory T-cell subsets was associated with lack of protection.

Conclusions:  Control of viral replication in a live-attenuated SIV vaccine context is associated with long-lived SIV-specific T cells with increased Bcl-2/caspase 3 ratio. The increased T-cell survival capacity likely allows maintenance of both CD4⁺ T-cell help and polyfunctional antiviral CD8⁺ T cells. Thus, a large proportion of effector memory T cells susceptible to apoptosis and less capable of sustained polyfunctional cytokine production may account for live-attenuated vaccine failure in the unprotected monkeys.