Sexual transmission of HIV infection to women occurs predominantly across cervicovaginal mucosal surfaces. Primate studies have shown that simian immunodeficiency virus (SIV) enters the epithelium of the vaginal mucosa and infects intraepithelial dendritic cells within 60 min of exposure to cell-free virus, with virus-infected cells appearing in local lymph nodes within 18 hrs.1 Virus-specific immune responses in genital mucosa are therefore likely to be critical for initial control of vaginal infection with HIV or SIV.
The presence of HIV- and SIV-specific T cells in the genital mucosa of women and female rhesus macaques has been reported by several groups. Kaul et al.2 demonstrated that HIV-specific CD8+ cytokine responses were lower in lymphocytes isolated from the cervix than in peripheral blood of HIV-infected women, whereas in exposed uninfected subjects, these responses were higher in cervix than in blood. Virus-specific cytotoxic T-cell activity has also been shown following in vitro stimulation of T cells isolated from cervical specimens from HIV-infected women3 and SIV-infected macaques.4 High frequencies of SIV-specific CD8+ T-cell responses were reported in cervicovaginal tissues in SIV-infected macaques5 and in macaques vaccinated with the live attenuated SHIV 89.6 vaccine.6 While these studies establish the presence of functional cellular immune responses in the female genital mucosa, they have provided only limited information regarding molecules mediating trafficking of virus-specific cells to genital mucosa.
The events that control trafficking of virus-specific lymphocytes into tissue compartments, and particularly genital mucosa, are incompletely understood. Molecules known to participate in this process include chemokines and their receptors, which have been shown to regulate lymphocyte traffic in normal and inflammed tissues.7 Chemokines produced in inflammation induce the migration of lymphocytes expressing CXCR3, CCR5, and other receptors for inflammatory chemokines into the inflamed tissues. This differential expression of chemokines by tissues has been implicated in the control of cytotoxic T lymphocyte (CTL) trafficking to sites of viral replication.8
In this study of SIV-infected female rhesus macaques, the frequency of CD8+ T cells specific for the immunodominant Mamu-A*01-restricted SIV Gag181–189 epitope9 was determined in blood, mucosal tissues, and secondary lymphoid organs by flow cytometry using peptide/MHC class I tetramers. SIV-specific CD8+ T cells were analyzed for expression of receptors known to participate in lymphocyte trafficking, including the chemokine receptors CXCR3, CXCR4, CCR5, and CCR7. SIV-specific CD8+ T cells in genital mucosa expressed high levels of CXCR3 and CCR5 relative to expression in peripheral blood. The results presented here demonstrate a significant enrichment of SIV-specific CD8+ T cells in the genital mucosa of infected female macaques and that inflammatory chemokines and their receptors play a role in directing cells to these tissues.