SPC3, a synthetic peptide derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120, inhibits HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms.
The third variable region (V3 loop) of gp120, the HIV-1 surface envelope glycoprotein, plays a key role in HIV-1 infection and pathogenesis. Recently, we reported that a synthetic multibranched peptide (SPC3) containing eight V3-loop consensus motifs (GPGRAF) inhibited HIV-1 infection in both CD4+ and CD4- susceptible cells. In the present study, we investigated the mechanisms of action of SPC3 in these cell types--i.e., CD4+ lymphocytes and CD4- epithelial cells expressing galactosylceramide (GalCer), an alternative receptor for HIV-1 gp120. We found that SPC3 was a potent inhibitor of HIV-1 infection in CD4+ lymphocytes when added 1 h after initial exposure of the cells to HIV-1, whereas it had no inhibitory effect when present only before and/or during the incubation with HIV-1. These data suggested that SPC3 did not inhibit the binding of HIV-1 to CD4+ lymphocytes but interfered with a post-binding step necessary for virus entry. In agreement with this hypothesis, SPC3 treatment after HIV-1 exposure dramatically reduced the number of infected cells without altering gp120-CD4 interaction or viral gene expression. In contrast, SPC3 blocked HIV-1 entry into CD4-/GalCer+ human colon epithelial cells when present in competition with HIV-1 but had no effect when added after infection. Accordingly, SPC3 was found to inhibit the binding of gp120 to the GalCer receptor. Thus, the data suggest that SPC3 affects HIV-1 infection by two distinct mechanisms: (i) prevention of GalCer-mediated HIV-1 attachment to the surface of CD4-/GalCer+ cells and (ii) post-binding inhibition of HIV-1 entry into CD4+ lymphocytes.
Yahi
N
N
Laboratoire des Protéines, Faculté de Médecine Nord, Centre National de la Recherche Scientifique, Marseille, France.
Fantini
J
J
Baghdiguian
S
S
Mabrouk
K
K
Tamalet
C
C
Rochat
H
H
Van Rietschoten
J
J
Sabatier
J M
JM
D015703:Antigens, CD / Q000502:physiology*; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000648:ultrastructure / Q000821:virology*; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure / Q000821:virology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D014764:Viral Proteins / Q000096:biosynthesis* / Q000302:isolation & purification
D015703:Antigens, CD; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D014764:Viral Proteins