NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal

Benjamin Trinité, Hongtao Zhang, David Levy

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Current efforts towards HIV-1 eradication focus on the reactivation and elimination of the latent viral reservoir, so-called shock and kill therapy. However, work from several groups indicates that infected cell death following virus reactivation is not guaranteed. Thus, it is imperative to develop strategies to foster specific elimination of cells carrying integrated proviruses. It has been shown that some non-nucleoside reverse transcriptase inhibitors (NNRTIs) including efavirenz can induce premature HIV-1 GagPol dimerization in productively infected cells, resulting in intracellular HIV-1 Protease (PR) activation and a reduction in HIV-1 expressing cells. RESULTS: Here, we document that NNRTI-induced PR activation triggers apoptotic death of productively infected resting or activated T cells in as little as 2 h via caspase-dependent and independent pathways. Rilpivirine, efavirenz and etravirine were the most potent NNRTIs, whereas nevirapine had almost no effect. NNRTI-induced cell killing was prevented by inhibitors of HIV-1 Protease (PR) activity including indinavir and nelfinavir. HIV-1 transmitter founder viruses induced cell killing similarly to lab-adapted HIV-1 except when NNRTI resistance conferring mutations were present in reverse transcriptase. Mutations in PR that confer PR inhibitor (PI) resistance restore NNRTI-induced killing in the presence of PI. Finally, we show that NNRTIs can rapidly eliminate cells in which latent viruses are stimulated to active expression. CONCLUSIONS: This work supports the notion that select NNRTIs might help promote the elimination of HIV-1 producing cells as an adjuvant during shock and kill therapy.

Original languageEnglish (US)
Number of pages1
JournalRetrovirology
Volume16
Issue number1
DOIs
StatePublished - Jun 26 2019

Fingerprint

HIV-1
T-Lymphocytes
efavirenz
Infection
Convulsive Therapy
Rilpivirine
etravirine
Viruses
Peptide Hydrolases
Nelfinavir
Indinavir
Nevirapine
Proviruses
Mutation
RNA-Directed DNA Polymerase
Dimerization
Caspases
Human immunodeficiency virus 1 p16 protease
Protease Inhibitors
Cell Death

Keywords

  • Cure therapy
  • HIV
  • Latent reservoir
  • NNRTI
  • Protease inhibitor

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal. / Trinité, Benjamin; Zhang, Hongtao; Levy, David.

In: Retrovirology, Vol. 16, No. 1, 26.06.2019.

Research output: Contribution to journalArticle

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