HIV-1 transmission by dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is regulated by determinants in the carbohydrate recognition domain that are absent in liver/lymph node-SIGN (L-SIGN).
In this study, we identify determinants in dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) necessary for human immunodeficiency virus, type 1 (HIV-1), transmission. Although human B cell lines expressing DC-SIGN efficiently capture and transmit HIV-1 to susceptible target cells, cells expressing the related molecule liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) do not. To understand the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions, we developed Raji B cell lines expressing different DC-SIGN/L-SIGN chimeras. Testing of the chimeras demonstrated that replacement of the DC-SIGN carbohydrate-recognition domain (CRD) with that of L-SIGN was sufficient to impair virus binding and prevent transmission. Conversely, the ability to bind and transmit HIV-1 was conferred to L-SIGN chimeras containing the DC-SIGN CRD. We identified Trp-258 in the DC-SIGN CRD to be essential for HIV-1 transmission. Although introduction of a K270W mutation at the same position in L-SIGN was insufficient for HIV-1 binding, an L-SIGN mutant molecule with K270W and a C-terminal DC-SIGN CRD subdomain transmitted HIV-1. These data suggest that DC-SIGN structural elements distinct from the oligosaccharide-binding site are required for HIV-1 glycoprotein selectivity.
Chung
Nancy P Y
NP
HIV Drug Resistance Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Breun
Sabine K J
SK
Bashirova
Arman
A
Baumann
Joerg G
JG
Martin
Thomas D
TD
Karamchandani
Jaideep M
JM
Rausch
Jason W
JW
Le Grice
Stuart F J
SF
Wu
Li
L
Carrington
Mary
M
Kewalramani
Vineet N
VN
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D050260:Carbohydrate Metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000378:metabolism* / Q000635:transmission*; D015497:HIV-1; D006801:Humans; D037102:Lectins / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human