Comparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups.
We have biologically and biochemically evaluated a structurally diverse group of HIV-1-specific reverse transcriptase (RT) inhibitors and determined that the members of this class share many common properties. These include reproducible and selective antiviral activity against a panel of biologically distinct laboratory and clinical strains of HIV-1, activity against HIV-1 in a wide variety of cultured and fresh human cells, and potent inhibition of HIV-1 RT when evaluated using a heteropolymeric ribosomal RNA template assay. Each of the HIV-1-specific compounds was capable of inhibiting HIV replication when challenged at high m.o.i., further distinguishing them from the nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). When tested in combination with AZT, each of the HIV-1-specific compounds synergistically inhibited the replication of HIV-1. HIV-1 isolates resistant to different HIV-1-specific inhibitors exhibited heterogeneous patterns of cross-resistance to other members of this pharmacologic class. Four distinct phenotypic classes have been defined through the use of drug-resistant virus isolates which derive from distinct mutations in the RT. These results indicate that the various subgroups of HIV-1-specific inhibitors interact differently with HIV-1 RT, suggesting important potential implications for drug combination therapeutic strategies.
Buckheit
R W
RW
Virology Research Group, Southern Research Institute-Frederick Research Center, MD 21701-4766, USA.
Fliakas-Boltz
V
V
Decker
W D
WD
Roberson
J L
JL
Stup
T L
TL
Pyle
C A
CA
White
E L
EL
McMahon
J B
JB
Currens
M J
MJ
Boyd
M R
MR
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004341:Drug Evaluation; D004347:Drug Interactions; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010641:Phenotype; D015203:Reproducibility of Results; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase