A paper from Chris Miller's research group at UC Davis reports that CD8 T cells can play a key role in protecting macaques against an intravaginal challenge with SIVmac239. The study employed a live-attenuated vaccine approach: macaques were immunized with an attenuated SIV/HIV hybrid (SHIV89.6) and then challenged 6-8 months later with the highly virulent SIVmac239. A subset of animals were depleted of CD8 T cells prior to challenge to explore the role of these responses in vaccine-mediated protection. At 14 days post-challenge, 9/9 controls and 4/12 immunized macaques were positive for SIV RNA in the plasma, and viral loads in the RNA-positive immunized animals were significantly lower than in the controls. All five immunized, CD8-depleted macaques showed detectable plasma SIV RNA and viral loads in these animals were significantly higher than in the other two groups.
The researchers also investigated the extent of post-challenge CD8 and CD4 T cell proliferation in the macaques, finding that expression of the Ki67 antigen remained stable in the immunized group but increased significantly in controls. Similarly, T cell apoptosis was increased in both controls and CD8-depleted animals but not in the immunized group. SIV-specific CD8 T cells were also significantly more polyfunctional and cytotoxic in both the blood and vagina of immunized macaques compared to the control and CD8-depleted groups. Notably, expansion of SIV-specific CD8 T cells occurred only in the vagina of vaccinees, and none of the five other compartments examined (including blood, lymph nodes and cervix). The researchers conclude that "the presence of SIV-specific CD8 T cells in the vagina on the day of vaginal SIV challenge and a modest expansion of effector T cells was sufficient to stop viral dissemination and uncontrolled SIV replication post-challenge." In discussing the results, they point out that these findings differ from those obtained with prime-boost vaccines, wherein SIV challenge typically leads to systemic proliferation of SIV-specific memory CD8 T cells, perhaps suggesting that induction of local effector CD8 T cells at the site of exposure should be the goal of T cell-based HIV vaccines.
JVI Accepts, published online ahead of print on 10 September 2008
J. Virol. doi:10.1128/JVI.01433-08
Meritxell Genescà, Pamela J. Skinner, Jung Joo Hong, Jun Li, Ding Lu, Michael B. McChesney, and Christopher J. Miller
Center for Comparative Medicine, California National Primate Research Center, University of California, Davis, Davis, CA, 95616 USA; Department of Veterinary and Biomedical Sciences, Department of Microbiology, University of Minnesota, St. Paul, MN, 55108 USA; Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine and Division of Infectious Diseases, School of Medicine, University of California, Davis, Davis, CA, 95616 USA
The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus (SHIV) 89.6 is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here we definitively demonstrate the protective role of the SIV-specific CD8+ T cell response in the SHIV-immunized monkeys by CD8+ lymphocyte depletion, an intervention that abrogated SHIV-mediated control of challenge virus replication and largely eliminated the SIV-specific T cell responses in blood lymph nodes and genital mucosa. While in the T cell intact SHIV- immunized animals, polyfunctional and degranulating SIV-specific CD8+ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 post-challenge. Strikingly, expansion of SIV-specific CD8+ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV 89.6 is primarily mediated by CD8+ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effector-cytotoxic CD8+ T cells can provide significant protection from vaginal SIV challenge.