Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates.
A non-cognate mechanism of protection against human immunodeficiency virus-1 (HIV-1) infection involves up-regulation of beta-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modified targeted lymph nodes (TLN) route with recombinant simian immunodeficiency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced significant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and down-modulation of the proportion of cells expressing CCR5 (r = 0.737, P<0.05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a significant inverse correlation with the CD8-SF or the concentration of the three beta-chemokines (r = 0.831 and 0.824, P<0.01), but a positive correlation between the proportion of CCR5+ cells and SIVmac RNA (r = 0.613, P = 0.05). These results demonstrate for the first time in vivo that immunization up-regulates beta-chemokines, which may down-modulate CCR5 co-receptors, and both functions are significantly correlated with the viral load. Hence, the non-cognate beta-chemokine-CCR5 mechanism should be considered as complementary to specific immunity in vaccination against HIV.
Lehner
T
T
Department of Immunobiology, Guy's, King's and St. Thomas' Hospitals, Medical and Dental Schools, London, UK.
Wang
Y
Y
Cranage
M
M
Tao
L
L
Mitchell
E
E
Bravery
C
C
Doyle
C
C
Pratt
K
K
Hall
G
G
Dennis
M
M
Villinger
L
L
Bergmeier
L
L
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism*; D015686:Gene Products, env / Q000235:genetics; D015683:Gene Products, gag / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006119:Groin; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000627:therapeutic use; D015847:Interleukin-4 / Q000627:therapeutic use; D008253:Macaca mulatta; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D009092:Mucous Membrane / Q000276:immunology; D012313:RNA / Q000032:analysis; D019713:Receptors, CCR5 / Q000378:metabolism*; D011994:Recombinant Proteins; D012007:Rectum; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins / Q000235:genetics; D019562:Viral Load; D014765:Viral Vaccines / Q000008:administration & dosage
D016827:CD8 Antigens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; C066594:Gag protein p27, Simian immunodeficiency virus; D015686:Gene Products, env; D015683:Gene Products, gag; D015699:HIV Envelope Protein gp120; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D014765:Viral Vaccines; C069623:gp120 protein, Simian immunodeficiency virus; C059580:transmembrane protein, Simian immunodeficiency virus; D015847:Interleukin-4; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor