HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death

We have tracked the in vivo migration and have identified in vivo correlate s of cytotoxic T-lymphocyte (CTL) activity in HIV-seropositive subjects inf used with autologous gene-marked CD8(+) HIV-specific CTL. The number of cir culating gene-marked CTL ranged from 1.6 to 3.5% shortly after infusion to less than 0.5% 2 weeks later. Gene-marked CTL were present in the lymph nod e at 4.5- to 11-fold excess and colocalized within parafollicular regions o f the lymph node adjacent to cells expressing HN fat fusion transcripts, a correlate of virus replication. The CTL clones expressed the CCR5 receptor and localized among HIV-infected cells expressing the ligands MIP-1 alpha a nd MIP-1 beta, CC-chemokines produced at sites of virus replication. Aggreg ates of apoptotic cells and cells expressing granzyme-B localized within th ese same sites. III contrast, lymph node sections from untreated HIV-seropo sitive subjects, all with significant viral burden (> 50,000 HIV RNA copies /mL plasma), showed no CC-chemokine expression and exhibited only sporadic and randomly distributed cells expressing granzymes and/or apoptotic cells. These studies show that the infused CTL specifically migrate to sites of H IV replication and retain their antigen-specific cytolytic potential. Moreo ver, these studies provide a methodology that will facilitate studies of bo th the magnitude and functional phenotype of Ag-specific CD8(+) T cells in vivo.