DC-SIGN interactions with human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus.
Dendritic cells (DCs) efficiently bind and transmit human immunodeficiency virus (HIV) to cocultured T cells and so may play an important role in HIV transmission. DC-SIGN, a novel C-type lectin that is expressed in DCs, has recently been shown to bind R5 HIV type 1 (HIV-1) strains and a laboratory-adapted X4 strain. To characterize the interaction of DC-SIGN with primate lentiviruses, we investigated the structural determinants of DC-SIGN required for virus binding and transmission to permissive cells. We constructed a panel of DC-SIGN mutants and established conditions which allowed comparable cell surface expression of all mutants. We found that R5, X4, and R5X4 HIV-1 isolates as well as simian immunodeficiency and HIV-2 strains bound to DC-SIGN and could be transmitted to CD4/coreceptor-positive cell types. DC-SIGN contains a single N-linked carbohydrate chain that is important for efficient cell surface expression but is not required for DC-SIGN-mediated virus binding and transmission. In contrast, C-terminal deletions removing either the lectin binding domain or the repeat region abrogated DC-SIGN function. Trypsin-EDTA treatment inhibited DC-SIGN mediated infection, indicating that virus was maintained at the surface of the DC-SIGN-expressing cells used in this study. Finally, quantitative fluorescence-activated cell sorting analysis of AU1-tagged DC-SIGN revealed that the efficiency of virus transmission was strongly affected by variations in DC-SIGN expression levels. Thus, variations in DC-SIGN expression levels on DCs could greatly affect the susceptibility of human individuals to HIV infection.
Pöhlmann
S
S
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Baribaud
F
F
Lee
B
B
Leslie
G J
GJ
Sanchez
M D
MD
Hiebenthal-Millow
K
K
Münch
J
J
Kirchhoff
F
F
Doms
R W
RW
D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D004492:Edetic Acid; D015870:Gene Expression; D006031:Glycosylation; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism*; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014357:Trypsin; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D004492:Edetic Acid; D037102:Lectins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D014357:Trypsin; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin