HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection.
All primate lentiviruses (HIV-1, HIV-2, SIV) encode Nef proteins, which are important for viral replication and pathogenicity in vivo. 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. Other studies suggest that Nef influences the activation state of the infected cell, thereby enhancing the ability of that cell to support viral replication. 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.
Swingler
Simon
S
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Brichacek
Beda
B
Jacque
Jean-Marc
JM
Ulich
Catherine
C
Zhou
Jin
J
Stevenson
Mario
M
D001402:B-Lymphocytes / Q000276:immunology; D018801:CD2 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D015693:Gene Products, nef / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D017455:Receptors, IgE / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D017735:Virus Latency; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D018801:CD2 Antigens; D019013:CD40 Antigens; D015693:Gene Products, nef; D017455:Receptors, IgE; D054311:nef Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens