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*
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021; and
Mount Sinai Medical School, New York, NY 10029
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-
(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.
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