Inhibition of human immunodeficiency virus type 1 by triciribine involves the accessory protein nef.
Triciribine (TCN) is a tricyclic nucleoside that inhibits human immunodeficiency virus type 1 (HIV-1) replication by a unique mechanism not involving the inhibition of enzymes directly involved in viral replication. This activity requires the phosphorylation of TCN to its 5' monophosphate by intracellular adenosine kinase. New testing with a panel of HIV and simian immunodeficiency virus isolates, including low-passage-number clinical isolates and selected subgroups of HIV-1, multidrug resistant HIV-1, and HIV-2, has demonstrated that TCN has broad antiretroviral activity. It was active in cell lines chronically infected with HIV-1 in which the provirus was integrated into chromosomal DNA, thereby indicating that TCN inhibits a late process in virus replication. The selection of TCN-resistant HIV-1 isolates resulted in up to a 750-fold increase in the level of resistance to the drug. DNA sequence analysis of highly resistant isolate HIV-1(H10) found five point mutations in the HIV-1 gene nef, resulting in five different amino acid changes. DNA sequencing of the other TCN-resistant isolates identified at least one and up to three of the same mutations observed in isolate HIV-1(H10). Transfer of the mutations from TCN-resistant isolate HIV-1(H10) to wild-type virus and subsequent viral growth experiments with increasing concentrations of TCN demonstrated resistance to the drug. We conclude that TCN is a late-phase inhibitor of HIV-1 replication and that mutations in nef are necessary and sufficient for TCN resistance.
Ptak
Roger G
RG
Department of Infectious Disease Research, Southern Research Institute, Frederick, Maryland 21701, USA.
Gentry
Brian G
BG
Hartman
Tracy L
TL
Watson
Karen M
KM
Osterling
M Clayton
MC
Buckheit
Robert W
RW
Townsend
Leroy B
LB
Drach
John C
JC
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D015754:Genes, nef; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D017354:Point Mutation; D012263:Ribonucleosides / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
D019380:Anti-HIV Agents; D012263:Ribonucleosides; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C023764:triciribine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase