Inhibition of HIV-1-induced syncytia formation and infectivity by lipophosphoglycan from Leishmania.
In HIV-1 infection, the appearance of syncytia-inducing (SI) isolates is associated with a more rapid decline of CD4+ cells and progression to AIDS. Agents that inhibit either virus infection or syncytia formation have the potential to be therapeutically useful. Lipophosphoglycan (LPG), the major glycoconjugate of Leishmania, was recently shown to be a potent nonspecific inhibitor of viral membrane fusion. In this study, LPG demonstrated a dose-dependent inhibition of HIV-1-induced syncytia formation in CD4+ MT-2 cells infected with distinct SI isolates. Fragments of LPG were used to show that inhibition of syncytia formation was dependent on the length of the LPG fragment. Treatment of CD4+ cells or HIV-1 isolates with LPG inhibited infection in vitro. Furthermore, LPG inhibited the replication of SI viral isolates in CD4+ T cells in vitro. LPG had no toxic effects on peripheral blood mononuclear cells at the highest concentrations used in these assays. Further, LPG rapidly associated with the surface membrane of a human T cell line and subsequently disassociated over a 24-h period. The development of compounds capable of inhibiting HIV-induced syncytia formation should provide novel therapeutic approaches to control the spread of virus and disease progression.
Easterbrook
M D
MD
Department of Pathology, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
Levy
M H
MH
Gomez
A M
AM
Turco
S J
SJ
Epand
R M
RM
Rosenthal
K L
KL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D002459:Cell Fusion / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015726:Giant Cells / Q000187:drug effects / Q000821:virology; D006028:Glycosphingolipids / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007893:Leishmania donovani / Q000737:chemistry*; D018320:Leishmania major / Q000737:chemistry*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D006028:Glycosphingolipids; C008290:lipophosphonoglycan