Serum inactivation contributes to the failure of stromal-derived factor-1 to block HIV-I infection in vivo.
The chemokine stromal-derived factor-1 (SDF-1) can block human immunodeficiency virus type 1 (HIV-1) infection in vitro by binding to the CXC chemokine receptor, CXCR-4, which serves as a coreceptor for T cell tropic HIV-1. In spite of being constitutively expressed in vivo, SDF-1 does not appear to block HIV-1 infection and spread in vivo. We report that SDF-1 is consistently measured in normal serum (15.4+/-3.0 ng/ml; mean+/-sd) and in serum from AIDS patients (16.6+/-3.7 ng/ml). However, we find that circulating SDF-1 is modified to an inactive form. When exposed to serum, recombinant SDF-1 is specifically and rapidly altered to yield an apparently smaller chemokine that does not bind to SDF-1 receptor-expressing cells, does not have chemoattractive or pre-B cell stimulatory activity, and does not block HIV-1 infection. Thus, serum modification and inactivation contribute to the failure of SDF-1 to block HIV-1 infection and spread in man. The inactivation of circulating SDF-1 may be critical in permitting local gradients to develop and direct cell trafficking.
Villalba
Sabrina
S
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Salvucci
Ombretta
O
Aoki
Yoshiyasu
Y
De La Luz Sierra
Maria
M
Gupta
Ghanshyam
G
Davis
David
D
Wyvill
Kathleen
K
Little
Richard
R
Yarchoan
Robert
R
Tosato
Giovanna
G
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000517:prevention & control*; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015497:HIV-1; D006801:Humans; D007074:Immunoglobulin G; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology* / Q000821:virology; D051379:Mice; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors; D012016:Reference Values; D017154:Stromal Cells / Q000502:physiology*; D014471:Umbilical Veins
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D007074:Immunoglobulin G; D023062:Receptors, Interleukin-8A