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 correlates of cytotoxic T-lymphocyte (CTL) activity in HIV-seropositive subjects infused with autologous gene-marked CD8(+) HIV-specific CTL. The number of circulating 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 node at 4.5- to 11-fold excess and colocalized within parafollicular regions of the lymph node adjacent to cells expressing HIV tat fusion transcripts, a correlate of virus replication. The CTL clones expressed the CCR5 receptor and localized among HIV-infected cells expressing the ligands MIP-1alpha and MIP-1beta, CC-chemokines produced at sites of virus replication. Aggregates of apoptotic cells and cells expressing granzyme-B localized within these same sites. In contrast, lymph node sections from untreated HIV-seropositive 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 HIV replication and retain their antigen-specific cytolytic potential. Moreover, these studies provide a methodology that will facilitate studies of both the magnitude and functional phenotype of Ag-specific CD8(+) T cells in vivo.
Brodie
S J
SJ
Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA. sjbrodie@u.washington.edu
Patterson
B K
BK
Lewinsohn
D A
DA
Diem
K
K
Spach
D
D
Greenberg
P D
PD
Riddell
S R
SR
Corey
L
L
D019264:Adoptive Transfer; D001483:Base Sequence; D016923:Cell Death; D002465:Cell Movement; D017931:DNA Primers / Q000235:genetics; D018014:Gene Transfer Techniques; D006678:HIV / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D006679:HIV Seropositivity / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D017403:In Situ Hybridization; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication
D017931:DNA Primers