Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Cell Rep. 2019 Jan 22;26(4):906-920.e3. doi: 10.1016/j.celrep.2018.12.095.


The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and microcephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested the concept that drugs targeting host proteostasis provide effective antivirals. We show that different cytosolic Hsp70 isoforms are recruited to ZIKV-induced compartments and are required for virus replication at pre- and post-entry steps. Drugs targeting Hsp70 significantly reduce replication of different ZIKV strains in human and mosquito cells, including human neural stem cells and a placental trophoblast cell line, at doses without appreciable toxicity to the host cell. By targeting several ZIKV functions, including entry, establishment of active replication complexes, and capsid assembly, Hsp70 inhibitors are refractory to the emergence of drug-resistant virus. Importantly, these drugs protected mouse models from ZIKV infection, reducing viremia, mortality, and disease symptoms. Hsp70 inhibitors are thus attractive candidates for ZIKV therapeutics with the added benefit of a broad spectrum of action.

Keywords: Hsp70; Hsp70 inhibitor; Zika virus; antiviral; chaperone; viral assembly; viral capsid; viral entry; viral replication complex.

Publication types

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

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Microcephaly / drug therapy
  • Microcephaly / metabolism
  • Microcephaly / pathology
  • Microcephaly / virology
  • Neural Stem Cells* / metabolism
  • Neural Stem Cells* / pathology
  • Neural Stem Cells* / virology
  • Virus Internalization / drug effects*
  • Virus Replication / drug effects*
  • Zika Virus / physiology*
  • Zika Virus Infection* / drug therapy
  • Zika Virus Infection* / metabolism
  • Zika Virus Infection* / pathology


  • Antiviral Agents
  • HSP70 Heat-Shock Proteins