Broad spectrum antiretroviral activity of 2',3'-dideoxynucleosides.

Abstract

Certain dideoxynucleosides have been shown to markedly inhibit the infectivity of human T-lymphotropic virus type m/lymphadenopathy-associated virus, the causative agent of acquired immunodeficiency syndrome (AIDS). Our present studies demonstrate that these drugs are broad spectrum antiretroviral agents capable of inhibiting the infectivity of evolutionarily divergent mammalian type C and animal lentiviruses. Under some conditions, virus infectivity could be inhibited by more than six orders of magnitude. However, the potency of these agents was shown to be greatly influenced by cell-specified determinants. Drug exposure during the initial 24 hr was almost as effective as prolonged treatment on the inhibition of a single cycle of virus infection and expression. Moreover, virus infection was shown directly to be inhibited at the level of proviral DNA synthesis. Thus the time period during which reverse transcription and provirus integration occur is the critical period required for drug action.Our findings have implications concerning strategies to be considered in attempts to utilize 2',3'-dideoxynucleosides in control and treatment of retrovirus-induced diseases ofanimals and humans.In the past few years, efforts aimed at prevention and control of retroviral-induced diseases have gained increasing importance with accumulating evidence that such viruses are responsible for human as well as animal diseases. A potentially useful strategy has arisen from the application of a group of nucleoside analogues first synthesized over 20 years ago (1-5). These dideoxynucleosides were shown to inhibit the retroviral reverse transcriptase (6-8) as well as cellular DNA polymerases f3 and y, while polymerase a was relatively resistant (8-12). Initial studies aimed at demonstrating selective inhibition of viral replication by these drugs showed relatively modest effects (7,8). Recently, however, 3'-azido-3'-deoxythymidine (N3dThd; sometimes referred to as AZT) (13) and virtually all of the 2',3'-dideoxynucleosides (14) analyzed were found to powerfully and selectively inhibit replication of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), § the retrovirus causative of acquired immunodeficiency syndrome (AIDS).The AIDS virus has been shown to be closely related to animal lentiviruses (15-17), whereas early investigations of these antiviral drugs focused upon distantly related type C viruses. Thus, it is not known whether the reported differences in their antiviral effects relate to host cell or viral specificities. Recently Mitsuya and his colleagues have shown that these nucleoside analogues act as chain terminators of the reverse transcription products of the incoming HTLV-III/LAV (18), although this need not be the only mechanism for antiretroviral activity. Our present studies demonstrate a broad spectrum of antiretroviral activity by these agents, but show considerable cell variation in the potency of different agents. Under optimal conditions, the selective inhibition of even a ...

Differential Susceptibility of Retroviruses to Nucleoside Analogues

“…Although these were all mammalian cell lines, different rates of drug uptake, phosphorylation and degradation cannot be excluded. Differences in the endogenous levels of the relevant kinases and phosphorylases required to transform the NRTIs into their active triphosphate (TP) form may exist in the different cell types (Dahlberg et al, 1987). For example, AZT is rapidly phosphorylated by cellular thymidine kinase (TK) to AZTmonophosphate (AZT-MP), which in turn, acts as a substrate for further catalysation to the di-and triphosphate forms (Lavie et al, 1997) by host cell thymidylate kinase (TdK) (Furman et al, 1986).…”

Pharmacological inhibition of in vitro infectivity of human T lymphotropic virus type I.

“…Recently we have learned that 2',3'-dideoxynucleoside analogues can profoundly suppress the replication of animal lentiviruses such as caprine arthritis-encephalitis virus and equine infectious anemia virus, as well as the focus formation induced by a transforming muine type C retrovirus, Kirsten murine sarcoma virus, in a system that requires only a single-round viral DNA formation and integration (46).…”

Human T-cell Lymphotropic Viruses: Review and Prospects for Antiviral Therapy

“…Earlier studies have shown that 2-,3'-deoxynucleosides have broad spectrum anti-retroviral activity against mammalian C-type and animallentiviruses (Dahlberg et a/., 1987). Moreover, mouse viremia and retroviral disease could be suppressed by AZT (Ruprecht et al, 1986).…”