Dual anti-HIV mechanism of clofarabine

Retrovirology. 2016 Mar 24:13:20. doi: 10.1186/s12977-016-0254-0.

Abstract

Background: HIV-1 replication kinetics inherently depends on the availability of cellular dNTPs for viral DNA synthesis. In activated CD4(+) T cells and other rapidly dividing cells, the concentrations of dNTPs are high and HIV-1 reverse transcription occurs in an efficient manner. In contrast, nondividing cells such as macrophages have lower dNTP pools, which restricts efficient reverse transcription. Clofarabine is an FDA approved ribonucleotide reductase inhibitor, which has shown potent antiretroviral activity in transformed cell lines. Here, we explore the potency, toxicity and mechanism of action of clofarabine in the human primary HIV-1 target cells: activated CD4(+) T cells and macrophages.

Results: Clofarabine is a potent HIV-1 inhibitor in both activated CD4(+) T cells and macrophages. Due to its minimal toxicity in macrophages, clofarabine displays a selectivity index over 300 in this nondividing cell type. The anti-HIV-1 activity of clofarabine correlated with a significant decrease in both cellular dNTP levels and viral DNA synthesis. Additionally, we observed that clofarabine triphosphate was directly incorporated into DNA by HIV-1 reverse transcriptase and blocked processive DNA synthesis, particularly at the low dNTP levels found in macrophages.

Conclusions: Taken together, these data provide strong mechanistic evidence that clofarabine is a dual action inhibitor of HIV-1 replication that both limits dNTP substrates for viral DNA synthesis and directly inhibits the DNA polymerase activity of HIV-1 reverse transcriptase.

Keywords: Clofarabine; Human immunodeficiency virus (HIV); Nucleoside/nucleotide analogue; Reverse transcription; Ribonucleotide reductase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / pharmacology*
  • Adenine Nucleotides / toxicity
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Antimetabolites / pharmacology*
  • Antimetabolites / toxicity
  • Arabinonucleosides / pharmacology*
  • Arabinonucleosides / toxicity
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Cell Survival / drug effects
  • Clofarabine
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Macrophages / drug effects*
  • Macrophages / virology
  • Virus Replication / drug effects

Substances

  • Adenine Nucleotides
  • Anti-HIV Agents
  • Antimetabolites
  • Arabinonucleosides
  • Clofarabine