Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection.
Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.
Casazza
Joseph P
JP
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA. jcasazza@mail.nih.gov
Brenchley
Jason M
JM
Hill
Brenna J
BJ
Ayana
Ribka
R
Ambrozak
David
D
Roederer
Mario
M
Douek
Daniel C
DC
Betts
Michael R
MR
Koup
Richard A
RA
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D010750:Phosphoproteins; D019713:Receptors, CCR5; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D054301:gag Gene Products, Human Immunodeficiency Virus