Dendritic cells, infected with vesicular stomatitis virus-pseudotyped HIV-1, present viral antigens to CD4+ and CD8+ T cells from HIV-1-infected individuals.
Nonreplicating vectors are being considered in HIV-1 vaccine design. However, nonreplicating viruses are typically weak immunogens, leading to efforts to target the vaccine to mature dendritic cells (DCs). We have studied a single-cycle form of HIV-1, prepared by pseudotyping envelope-defective HIV-1 plasmids with the envelope from vesicular stomatitis virus (VSV) G protein (VSV-G), to which most humans lack preexisting immunity. The nonreplicating, VSV/HIV-1 efficiently infected the immature stage of DC development, in this case represented by monocytes cultured with GM-CSF and IL-4. A majority of the cells reverse transcribed the HIV-1 RNA, and a minority expressed gag protein. The infected populations were further matured with CD40 ligand, leading to strong stimulation of autologous T cells from HIV-1-infected individuals, but not controls. Enriched CD8(+) T cells from 12/12 donors released IFN-gamma (50-300 enzyme-linked immunospots/200,000 T cells) and proliferated. Macrophages were much less efficient in expanding HIV-1-responsive T cells, and bulk mononuclear cells responded weakly to VSV/HIV-1. CD4(+) T cells from at least half of the donors showed strong responses to VSV/HIV-1-infected DCs. Presentation to CD8(+) T cells, but not to CD4(+), was primarily through an endogenous pathway, because the responses were markedly reduced if envelope-defective virus particles or reverse transcriptase inhibitors were added. Therefore, nonreplicating vaccines can be targeted to immature DCs, which upon further maturation induce combined and robust CD4(+) and CD8(+) immunity.
Granelli-Piperno
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A
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021. Mount Sinai Medical School, New York, NY 10029, USA. Piperno@rockvax.rockefeller.edu
Zhong
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L
Haslett
P
P
Jacobson
J
J
Steinman
R M
RM
D000328:Adult; D017951:Antigen Presentation / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000276:immunology; D016655:HIV Core Protein p24 / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics* / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24