Mechanistic effect of NMSO3 on replication of human immunodeficiency virus.
NMSO3, a sulphated sialyl lipid, was evaluated for its efficacy against human immunodeficiency virus type 1 (HIV-1). The compound exhibited concentration-dependent inhibition of HIV-1 replication in primary infection cell culture systems. Substantial inhibition was observed at concentrations of NMSO3 that showed little cytotoxicity. NMSO3 also exhibited anti HIV-1 activity in chronically HIV-1 infected cultures. The production of progeny viruses was completely abolished without cytotoxicity by continuous addition of NMSO3 to chronically infected U937 cells. Furthermore, in attempting to define the inhibitory mechanism of NMSO3, we investigated its effect on several steps of the HIV-1 replication cycle. NMSO3 competes with gp120 for binding to CD4 receptors on cells and inhibits the entry of HIV-1. By epitope analysis of the human CD4 molecule, NMSO3 inhibits the binding of antibodies, which recognize the D1 domain of CD4. Moreover, semi-quantitative reverse transcribed polymerase chain reaction (RT-PCR) showed that the integrated provirus is transcriptionally inactive in NMSO3-treated cells, supporting the lack of progeny in the culture supernatant of chronically HIV-1-infected cells treated with NMSO3. These findings indicate that NMSO3 has a unique mechanism of action against HIV-1 in both primary and chronic infection, and may be a valuable compound for the treatment of HIV-1 infection.
Department of Microbiology, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461 Japan. nakamura@jikei.ac.jp
Mariko
M
Nakamura
Masaki
M
Terada
Minori
M
Kamada
Akira
A
Yokono
Shogo
S
Nakamori
Tsuneya
T
Ohno
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000633:toxicity; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000494:pharmacology* / Q000633:toxicity; D015394:Molecular Structure; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D015728:Receptors, HIV / Q000378:metabolism; D013997:Time Factors; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
C413863:(2,2-bis(docosyloxymethyl)propyl-5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium oxysulfonyl)glycero-alpha-galacto-2-nonulopyranosid)onate; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008055:Lipids; D015728:Receptors, HIV; D015215:Zidovudine; D019158:N-Acetylneuraminic Acid