Journal
NATURE
Volume 424, Issue 6945, Pages 213-219Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature01749
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Funding
- NIAID NIH HHS [R01 AI037475, R01 AI032890] Funding Source: Medline
- NIMH NIH HHS [R01 MH064411, R01 MH093306] Funding Source: Medline
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All primate lentiviruses (HIV-1, HIV-2, SIV) encode Nef proteins, which are important for viral replication and pathogenicity in vivo(1-3). It is not known how Nef regulates these processes. It has been suggested that Nef protects infected cells from apoptosis and recognition by cytotoxic T lymphocytes(4-6). Other studies suggest that Nef influences the activation state of the infected cell, thereby enhancing the ability of that cell to support viral replication(7-10). Here we show that macrophages that express Nef or are stimulated through the CD40 receptor release a paracrine factor that renders T lymphocytes permissive to HIV-1 infection. This activity requires the upregulation of B-cell receptors involved in the alternative pathway of T-lymphocyte stimulation. T lymphocytes stimulated through this pathway become susceptible to viral infection without progressing through the cell cycle. We identify two proteins, soluble CD23 and soluble ICAM, that are induced from macrophages by Nef and CD40L, and which mediate their effects on lymphocyte permissivity. Our results reveal a mechanism by which Nef expands the cellular reservoir of HIV-1 by permitting the infection of resting T lymphocytes.
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