Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4 + T cell activation and HIV-1 latency reversal

Sci Adv. 2019 Mar 27;5(3):eaav6322. doi: 10.1126/sciadv.aav6322. eCollection 2019 Mar.

Abstract

A proposed strategy to cure HIV uses latency-reversing agents (LRAs) to reactivate latent proviruses for purging HIV reservoirs. A variety of LRAs have been identified, but none has yet proven effective in reducing the reservoir size in vivo. Nanocarriers could address some major challenges by improving drug solubility and safety, providing sustained drug release, and simultaneously delivering multiple drugs to target tissues and cells. Here, we formulated hybrid nanocarriers that incorporate physicochemically diverse LRAs and target lymphatic CD4+ T cells. We identified one LRA combination that displayed synergistic latency reversal and low cytotoxicity in a cell model of HIV and in CD4+ T cells from virologically suppressed patients. Furthermore, our targeted nanocarriers selectively activated CD4+ T cells in nonhuman primate peripheral blood mononuclear cells as well as in murine lymph nodes, and substantially reduced local toxicity. This nanocarrier platform may enable new solutions for delivering anti-HIV agents for an HIV cure.

Publication types

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

MeSH terms

  • Animals
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / chemistry
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Chemical Phenomena
  • Drug Carriers / chemistry
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / immunology
  • HIV-1 / physiology
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Macaca
  • Mice, Inbred C57BL
  • Nanostructures / administration & dosage*
  • Nanostructures / chemistry
  • Virus Latency / drug effects*
  • Virus Latency / immunology

Substances

  • Anti-HIV Agents
  • Drug Carriers