Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro

Abstract

Combinations of 3'-azido-3'-deoxythymidine and phosphonoformate produced a moderate synergistic inhibitory effect against human immunodeficiency virus type 1 in vitro at concentrations that are easily achieved in humans. The synergistic effect was more pronounced with increasing concentrations and was not secondary to toxic effects of the drugs. 3'-Azido-3'-deoxythymidine neither inhibited the replication of human cytomegalovirus in human embryonic lung fibroblasts nor interfered with the anticytomegalovirus effect of phosphonoformate. By using partially purified reverse transcriptase of human immunodeficiency virus type 1 and human cytomegalovirus DNA polymerase, various combinations of 3'-azido-3'-deoxythymidine-5'-triphosphate and phosphonoformate produced strong indications of additive interactions. The synergistic interactions in infected cells and the additive effects observed at the reverse transcriptase level indicate that mechanisms other than the reverse transcriptase may be of importance for the inhibition of human immunodeficiency virus replication by these two compounds. A concomitant treatment of cytomegalovirus infections, such as cytomegalovirus retinitis, with phosphonoformate in patients with acquired immunodeficiency syndrome receiving 3'-azido-3'-deoxythymidine may be appropriate, and this combination may also be useful in controlling human immunodeficiency virus infection.

Relationship between 3′-Azido-3′-Deoxythymidine Resistance and Primer Unblocking Activity in Foscarnet-Resistant Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

“…On structural grounds, the site of interaction for PP i (and, presumably, for foscarnet) should lie within the deoxynucleoside triphosphate (dNTP) binding site since PP i is formed from the ␤ and ␥ phosphates of the dNTP substrate, but foscarnet inhibition of DNA synthesis in vitro is noncompetitive with dNTP substrates (58), indicating that foscarnet and dNTP bind to distinguishable forms of RT. In addition, median-effect analysis comparing foscarnet and 3Ј-azido-3Ј-deoxythymidine (AZT) triphosphate (AZTTP) alone or as mixtures has shown that inhibition by these compounds is mutually exclusive (10, 22, 50), implying that binding of either inhibitor prevents binding of the other to the same enzyme molecule.In intact cells, the inhibition of HIV-1 by foscarnet and AZT is synergistic (10,22). The mechanism of this synergy is unclear, but it has recently been demonstrated that AZT monophosphate (AZTMP) incorporation can be reversed by the primer-unblocking activity of RT, in which the chain-terminating residue is transferred to an acceptor substrate such as PP i or an NDP or NTP (1, 4, 32, 34).…”

Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine in the Presence of Ganciclovir or Foscarnet

“…Furthermore, administration of both GCV and AZT to CMV-infected AIDS patients in clinical trials has revealed the increased toxicity of this combination (Jacobson et ei., 1988b;Hochster et al, 1990;Millar et el., 1990; Studies of ocular complications of AIDS research group, 1992). Conversely, the combination of PFA and AZT synergistically inhibits HIV replication in vitro (Eriksson and Schinazi, 1989;Koshida et el., 1989;Kong et et., 1991). A clinical trial comparing GCV and PFA for treatment of CMV retinitis in AIDS patients showed PFA to have a survival benefit over GCV, even after correction for the length of anti-retroviral therapy (Studies of ocular complications of AIDS research group, 1992).…”

Foscarnet Decreases Human Immunodeficiency Virus RNA

“…In vitro data suggest that the inhibition of HIV replication by foscamet and zidovudine is synergistic [1,2]. In our study, it is interesting that the 2 patients receiving zidovudine during foscamet treatment had the largest decrease in HIV viremia (-1.49 and -1.53 log RNA/mL).…”

“…Foscamet (sodium salt of phosphonoformic acid) is, in vitro, a noncompetitive inhibitor of human immunodeficiency virus (HIV) reverse transcriptase and decreases HIV replication [1,2]. In AIDS patients treated with foscamet for cytomegalovirus (CMV) retinitis, a decrease in p24 antigenemia was observed, suggesting an inhibition of HIV replication in vivo [3,4].…”