Differential susceptibility of retroviruses to nucleoside analogues.
Retroviruses may cause diseases in their vertebrate hosts. They are distinguished by their common means of replication involving reverse transcription, a process inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and other compounds used in antiretroviral chemotherapy. Previous work on NRTIs has been limited to their effect on human immunodeficiency virus (HIV) (for review see Ho & Hitchcock, 1989; Weller, 1999) and little information exists regarding the efficacy and therapeutic potential of these drugs against other retroviruses. We have tested all six NRTIs licensed for HIV treatment [didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), zidovudine (AZT) and abacavir (ABC)] against seven retroviruses representative of the traditional subfamilies: Spumavirinae, Lentivirinae and the Oncovirinae. As expected, each drug showed a range of activities against the panel of retroviruses, some drugs inhibiting other viruses at concentrations well below those required for HIV. Overall, AZT was the most active inhibitor (IC50 range, 0.032-1.0 microM), being most active against the Spuma (foamy) viruses. Abacavir was inhibitory for HIV-1, MN strain (HIV-1 MN), amphotrophic murine leukemia virus (MLV-A) and simian foamy virus type 6 (SFV-6). The least effective inhibitor, 3TC (IC50 range, 0.32->100 microM), was most potent against simian retrovirus types 1 and 2 (SRV-1, SRV-2) and HIV-1, but did not inhibit foamy viruses and MLV-A. Additionally, there were differences in the concentration of drug required to inhibit closely related viruses. Taken together, these data suggest that NRTIs have a wide spectrum of antiretroviral activity and the activity of compounds, even against closely related retroviruses, cannot be predicted.
Rosenblum
L L
LL
Department of GU Medicine & Communicable Diseases, Imperial College School of Medicine, at St Marys, London, UK.
Patton
G
G
Grigg
A R
AR
Frater
A J
AJ
Cain
D
D
Erlwein
O
O
Hill
C L
CL
Clarke
J R
JR
McClure
M O
MO
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D016049:Didanosine / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D019259:Lamivudine / Q000494:pharmacology / Q000633:toxicity; D008907:Mink; D009705:Nucleosides / Q000494:pharmacology* / Q000633:toxicity; D012190:Retroviridae / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D018119:Stavudine / Q000494:pharmacology / Q000633:toxicity; D013379:Substrate Specificity; D016047:Zalcitabine / Q000494:pharmacology / Q000633:toxicity; D015215:Zidovudine / Q000494:pharmacology / Q000633:toxicity
D000998:Antiviral Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D016047:Zalcitabine; D018119:Stavudine; D016049:Didanosine