Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells.
BACKGROUND
To initiate immunity, dendritic cells (DCs) capture antigens or viruses at body surfaces, undergo maturation to express T-cell costimulatory molecules, and then migrate to lymphoid organs. DCs at body surfaces can capture human immunodeficiency virus 1 (HIV-1), but mature DCs do not support replication of the virus unless T cells are added. The initial site for HIV-1 replication remains unknown and it is unclear whether replication can take place in DCs or whether the virus must first be transmitted from DCs to T cells.


RESULTS
We generated mature DCs from monocyte precursors. Upon infection with HIV-1, reverse transcription was completed only when T cells were added. When the reverse transcriptase inhibitor azidothymidine was added to the DCs during exposure to HIV-1, the DCs remained fully infectious, as long as the drug was removed just before culturing the DCs with T cells. HIV-1 variants that were engineered to undergo only one cycle of replication were able to infect DCs and replicate once in these cells. When T cells were added, newly produced HIV-1 Gag protein was exclusively localized to the DCs. With wild-type virus, subsequent rounds of replication took place in T cells. Soluble CD40 ligand (CD40L) and CD40L-transfected fibroblasts stimulated HIV-1 replication in purified mature DCs.


CONCLUSIONS
Mature DCs provide a drug-resistant reservoir for HIV-1. This reservoir is activated within DCs by CD40L and upon interaction with T cells, and the virus then spreads rapidly to other T cells.
Granelli-Piperno
A
A
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York 10021-6399, USA. piperno@rockvax.rockefeller.edu
Finkel
V
V
Delgado
E
E
Steinman
R M
RM
D019380:Anti-HIV Agents / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured / Q000821:virology; D018920:Coculture Techniques / Q000379:methods; D003713:Dendritic Cells / Q000821:virology*; D015683:Gene Products, gag / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D013601:T-Lymphocytes / Q000821:virology*; D014764:Viral Proteins / Q000032:analysis; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D019013:CD40 Antigens; D015683:Gene Products, gag; D014764:Viral Proteins; D015215:Zidovudine