An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation

Antiviral Res. 2016 Dec;136:51-59. doi: 10.1016/j.antiviral.2016.11.001. Epub 2016 Nov 5.

Abstract

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif. Antiviral activity depended on the expression of the cellular viral restriction factor APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that O2-16 has low cytotoxicity and inhibits Vif-dependent A3G degradation, enabling A3G packaging into HIV viral particles that results in A3G signature hypermutations in viral genomes. This antiviral activity was A3G-dependent and broadly neutralizing against sixteen HIV clinical isolates from groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Molecular modeling predicted binding near the PPLP motif crucial for Vif multimerization and activity. O2-16 also was active in blocking Vif degradation of APOBEC3F (A3F). We propose that CPT analogs not active against TOP1 have novel therapeutic potential as Vif antagonists that enable A3G-dependent hypermutation of HIV.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • APOBEC-3G Deaminase / genetics
  • APOBEC-3G Deaminase / metabolism*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Cell Line
  • DNA Topoisomerases, Type I / metabolism*
  • Drug Resistance, Viral / genetics
  • Genome, Viral
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / physiology
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Multimerization / drug effects
  • Virion / metabolism
  • Virus Replication
  • vif Gene Products, Human Immunodeficiency Virus / chemistry
  • vif Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • Camptothecin