Synergistic combinations and peptides in the inhibition of human immunodeficiency virus.
Various combinations of inhibitors of HIV reverse transcriptase were tested for inhibition of HIV replication in order to reveal any potential synergism or antagonism. PFA, a pyrophosphate analogue, gave synergistic inhibition of HIV replication in combination with both of the thymidine analogues AZT and FLT. The combination of PFA and AZT-TP gave only additive or weakly synergistic inhibition in a reverse transcriptase enzyme assay. The combination of AZT and FLT also gave synergistic inhibition of HIV replication, whilst the combination of AZT-TP and FLT-TP gave only additive or weakly synergistic inhibition of reverse transcriptase. Thus, the synergy does not arise from effects on reverse transcriptase alone but must be owing to other, cellular factors, such as effects on nucleoside metabolism or metabolism of the analogues. The results are consistent with the hypothesis that AZT may have an alternative mechanism of inhibition other than inhibition of reverse transcriptase. The diminished cytotoxicity observed in addition to the synergistic inhibition makes these combinations attractive from the point of view of combination chemotherapy. The inhibition of HIV replication by peptides from various parts of the V3 region of gp120 whose sequences were homologous with the tryptase inhibitor trypstatin was tested. Inhibitory activity was displayed by two peptides containing cysteine in their sequence. Antibodies to two peptides containing the two conserved cysteine residues from opposite sides of the neutralizing loop of gp120 were previously associated with protection from vertical transmission of HIV. The V3 region thus seems to be important for the function of gp120 and the transmission of HIV.
Cox
S
S
Department of Virology, National Bacteriological Laboratory, Stockholm, Sweden.
Koshida
R
R
Harmenberg
J
J
Wahren
B
B
D000510:Alpha-Globulins; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004357:Drug Synergism; D017245:Foscarnet; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011506:Proteins; D018894:Reverse Transcriptase Inhibitors; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology*
D000510:Alpha-Globulins; D000998:Antiviral Agents; D015224:Dideoxynucleosides; D009842:Oligopeptides; D011506:Proteins; D018894:Reverse Transcriptase Inhibitors; D015842:Serine Proteinase Inhibitors; C016001:alpha-1-microglobulin; D017245:Foscarnet; D015215:Zidovudine; D010746:Phosphonoacetic Acid; C002854:alovudine