MS-8209, a new Amphotericin B derivative that inhibits HIV-1 replication in vitro and restores T-cell activation via the CD3/TcR in HIV-infected CD4+ cells.
A new Amphotericin B derivative, MS-8209, which retains high antifungal activity with greatly reduced toxicity and improved solubility, has been developed. We investigated the antiviral properties of MS-8209 in Jurkat and CEM T-cell lines and in peripheral blood mononuclear cells infected in vitro with HIV-1BRU. Our results demonstrate, by determination of reverse transcriptase activity and p24 antigen level titration in cell culture supernatants, that MS-8209 inhibits HIV-1 replication in all cell types at concentrations without cytotoxicity. MS-8209 also prevents membrane expression of the HIV-1 large envelope glycoprotein gp120 and the decrease in CD4 level at the surface of infected cells. HIV-1-infected Jurkat cells exhibit a severe signalling defect at CD3 stimulation. Treatment with MS-8209 restores normal responsiveness at CD3 as assessed by measurement of inositol triphosphate accumulation and calcium flux. Finally, our results indicate that MS-8209 inhibits HIV-1BRU replication without preventing virus binding and penetration into target cells.
Céfai
D
D
Laboratoire d'Immunologie Cellulaire et Tissulaire, CERVI, La Pitié-Salpêtrière, Paris, France.
Hadida
F
F
Jung
M
M
Debre
P
P
Vernin
J G
JG
Seman
M
M
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D000998:Antiviral Agents / Q000494:pharmacology*; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D002460:Cell Line; D016655:HIV Core Protein p24 / Q000032:analysis; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D000945:Antigens, Differentiation, T-Lymphocyte; D000998:Antiviral Agents; D017252:CD3 Complex; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D011948:Receptors, Antigen, T-Cell; C074660:MS 8209; D000666:Amphotericin B; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D010738:Type C Phospholipases