Although it is now clear that the induction of CD8+
T-lymphocyte responses is associated with the containment of HIV/SIV replication (5
), how these cells mediate this antiviral effect in vivo has not yet been defined fully. Thus, while CTL killing is important for the long-term control of human T-lymphotropic virus type 1 and CD8+
T-lymphocyte production of IFN-γ is critical for hepatitis B virus containment, the phenotypic and functional profiles of the T-cell populations that control primate lentivirus replication in vivo remain poorly characterized.
The present study defines the virus-specific cellular immune correlates of protection against primate immunodeficiency viruses in the SIV-macaque model. Because we monitored a large cohort of monkeys for 850 days after infection, we were able to use survival as an end point in this study. Moreover, by evaluating vaccinated monkeys that were subsequently challenged with pathogenic virus, we were able to assess the contributions of virus-specific immune functions to protection in two different settings. We characterized the contribution of immune responses generated through vaccination prior to infection as well as the contribution of immune responses generated in the face of ongoing viral replication.
The vaccination regimens elicited high-frequency SIV-specific cellular immune responses, with greater responses detected in the monkeys that received the DNA prime-rAd boost regimen than in those that received only rAd immunizations (16
). After virus challenge, there were no statistically significant differences in cellular immune responses between the various groups of experimentally vaccinated monkeys. In fact, animals vaccinated with the Env constructs alone had robust Gag responses. We presume that the Env vaccine protected the monkeys from memory CD4+
T-cell loss, thus preserving CD4 help for the generation of Gag-specific CD8+
T-cell responses following SIV infection. All 24 experimentally vaccinated monkeys were treated as a single group and were compared to the 6 sham-vaccinated control monkeys, as shown in Fig. and .
Little work has been done previously to define the quality of memory T cells required for protection against primate immunodeficiency virus-induced disease. Since central memory CD8+
T cells have been implicated in protection against disease in murine infection models (29
), we hypothesized that the same may be true for SIV-infected rhesus monkeys. In this study, we show that survival was associated with vaccine-induced CD8+
T cells and was also associated with the preservation of Gag-specific central memory, but not effector memory, CD8+
T-cell responses following SIV challenge. The protection conferred by virus-specific central memory CD8+
T cells may be explained by their proliferative capacity upon encountering antigen. Central memory CD8+
T cells can recognize viral antigen and proliferate to generate a large pool of secondary effector cells. Such secondary effector cells may then mediate anti-SIV activity. Whatever mechanism is used, the present findings suggest that the SIV-specific central memory CD8+
T cells play a critical role in protecting vaccinated, infected monkeys against disease progression.
Given the importance of CD4+
T lymphocytes in potentiating the function of CD8+
T lymphocytes (10
), it was important to evaluate the contribution of CD4+
T lymphocytes to the containment of SIV replication and the prolongation of survival in this cohort of monkeys. In fact, we previously reported that survival following challenge in this cohort of monkeys was associated with preserved peripheral blood central memory CD4+
T-cell counts. Moreover, we also showed that survival was associated with vaccine-elicited SIV Gag-specific CD4+
T-cell IFN-γ responses before challenge (16
). We built upon these observations in the present study by showing that preserved SIV-stimulated CD4+
T-cell production of IFN-γ, TNF-α, and IL-2 was associated with prolonged survival in the infected monkeys. Importantly, we also show an association between the magnitude of SIV-specific central memory CD8+
T-cell cytokine responses and the preservation of SIV-specific CD4+
T-cell help. These findings underscore the critical importance of virus-specific CD4+
T-cell help in the generation and maintenance of long-lived virus-specific central memory CD8+
Recent studies have shown that HIV-1-infected clinical nonprogressors maintain virus-specific CD8+
T cells with a larger functional repertoire than that of cells from clinical progressors (4
). In the present study, we show that the functional profile of SIV Gag-specific CD8+
T cells from control vaccinated monkeys was largely limited to the expression of IFN-γ, while the virus-specific CD8+
T cells of vaccinated monkeys retained the capacity to produce IFN-γ, TNF-α, and IL-2. These findings suggest that the preservation of multifunctional populations of virus-specific T cells will be associated with protection against disease progression in vaccinated, infected monkeys. To what extent the preservation of the multifunctionality of the virus-specific T lymphocytes represents a cause or a consequence of the improved clinical status of the vaccinated monkeys remains to be determined.