A fusion inhibitor prevents spread of immunodeficiency viruses, but not activation of virus-specific T cells, by dendritic cells.
Dendritic cells (DCs) play a key role in innate immune responses, and their interactions with T cells are critical for the induction of adaptive immunity. However, immunodeficiency viruses are efficiently captured by DCs and can be transmitted to and amplified in CD4(+) T cells, with potentially deleterious effects on the induction of immune responses. In DC-T-cell cocultures, contact with CD4(+), not CD8(+), T cells preferentially facilitated virus movement to and release at immature and mature DC-T-cell contact sites. This occurred within 5 min of DC-T-cell contact. While the fusion inhibitor T-1249 did not prevent virus capture by DCs or the release of viruses at the DC-T-cell contact points, it readily blocked virus transfer to and amplification in CD4(+) T cells. Higher doses of T-1249 were needed to block the more robust replication driven by mature DCs. Virus accumulated in DCs within T-1249-treated cocultures but these DCs were actually less infectious than DCs isolated from untreated cocultures. Importantly, T-1249 did not interfere with the stimulation of virus-specific CD4(+) and CD8(+) T-cell responses when present during virus-loading of DCs or for the time of the DC-T-cell coculture. These results provide clues to identifying strategies to prevent DC-driven virus amplification in CD4(+) T cells while maintaining virus-specific immunity, an objective critical in the development of microbicides and therapeutic vaccines.
Frank
I
I
Center for Biomedical Research, Population Council, New York, New York 10065, USA.
Stössel
H
H
Gettie
A
A
Turville
S G
SG
Bess
J W
JW
Lifson
J D
JD
Sivin
I
I
Romani
N
N
Robbiani
M
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000648:ultrastructure / Q000821:virology; D005260:Female; D006678:HIV / Q000502:physiology*; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000648:ultrastructure; D013997:Time Factors
D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C474741:peptide T1249