Human CD38 interferes with HIV-1 fusion through a sequence homologous to the V3 loop of the viral envelope glycoprotein gp120.
CD38 is a progression marker in HIV-1 infection, it displays lateral association with CD4, and down-modulates gp120/CD4 binding. The aim of this study was to elucidate the mechanism behind the interplay between CD4, CD38, and HIV-1. We used mouse cell transfectants expressing human CD4 and either CD38 or other CD4-associated molecules to show that CD38 specifically inhibits gp120/CD4 binding. Human cell transfectants expressing truncated forms of CD38 and bioinformatic analysis were used to map the anti-HIV activity and show that it is concentrated in the membrane-proximal region. This region displayed significant sequence-similarity with the V3 loop of the HIV-1 gp120 glycoprotein. In line with this similarity, synthetic soluble peptides derived from this region reproduced the anti-HIV effects of full-length CD38 and inhibited HIV-1 and HIV-2 primary isolates from different subtypes and with different coreceptor use. A multiple-branched peptide construct presenting part of the sequence of the V3-like region potently and selectively inhibited HIV-1 replication in the nanomolar range. Conversely, a deletion in the V3-like region abrogated the anti-HIV-1 activity of CD38 and its lateral association with CD4. These findings may provide new insights into the early events of HIV-1 fusion and strategies to intervene.
Savarino
Andrea
A
Laboratory of Immunology, Interdisciplinary Research Center of Autoimmune Diseases, Department of Medical Science, University of Eastern Piedmont, Novara, Italy. asavarino@medscape.com
Bensi
Thea
T
Chiocchetti
Annalisa
A
Bottarel
Flavia
F
Mesturini
Riccardo
R
Ferrero
Enza
E
Calosso
Liliana
L
Deaglio
Silvia
S
Ortolan
Erika
E
Buttò
Stefano
S
Cafaro
Aurelio
A
Katada
Toshiaki
T
Ensoli
Barbara
B
Malavasi
Fabio
F
Dianzani
Umberto
U
D036541:ADP-ribosyl Cyclase / Q000737:chemistry* / Q000235:genetics; D051997:ADP-ribosyl Cyclase 1; D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics; D015704:CD4 Antigens / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D006801:Humans; D008561:Membrane Fusion; D008562:Membrane Glycoproteins; D051379:Mice; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
D015703:Antigens, CD; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D008562:Membrane Glycoproteins; D010455:Peptides; D011991:Receptors, Virus; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1