Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.
A new class of membrane-active ether lipid (EL) analogs of platelet-activating factor were studied for in vitro anti-HIV-1 activity. Human T-cell (CEM-ss) monolayers or suspension cultures were used to determine effects of structural modifications of Type A phosphorus-containing and Type B nonphosphorus EL analogs on (a) the inhibitory concentration50 (IC50) for HIV-1 syncytial plaque formation and cell growth, and, (b) virus budding at the cell plasma membrane. Results indicate that representative Type A and Type B EL inhibit HIV-1 but not herpes simplex virus type 2 plaque formation when added before or up to 2 days after viral infection. Anti-HIV-1 activity does not involve direct inactivation of virus infectivity. Type A EL (IC50 range = 0.2-1.4 microM) with alkyoxy, alkylthio, or alkyamido substitution at glycerol position 1 and ethoxy or methoxy substitution at position 2, and Type B compounds (IC50 range = 0.33-0.63 microM) with an inverse choline or nitrogen heterocyclic substitution at position 3 have selective activity against HIV-1-infected T-cells. EL treatment of HIV-1-infected cells is associated with subsequent release of reverse transcriptase activity, but infectious virus production is inhibited with time after infection. Electron microscopic examination of HIV-1-infected and EL-treated cells revealed absence of detectable budding virus at the plasma membrane but presence of intracytoplasmic vacuolar virus particles. In summary, these data suggest that EL analogs are a novel class of agents that induce defective intracytoplasmic vacuolar HIV-1 formation in T-cells. Being membrane interactive, EL are ideally suited for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs.
Department of Microbiology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103.
L S
LS
Kucera
N
N
Iyer
E
E
Leake
A
A
Raben
E J
EJ
Modest
L W
LW
Daniel
C
C
Piantadosi
D002462:Cell Membrane / Q000382:microbiology; D003673:Defective Viruses / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D008055:Lipids / Q000494:pharmacology*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000032:analysis; D014779:Virus Replication / Q000187:drug effects*
D008055:Lipids; D010742:Phospholipid Ethers; D012194:RNA-Directed DNA Polymerase