Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape

Ross A. Pollack, R. Brad Jones, Mihaela Pertea, Katherine M. Bruner, Alyssa R. Martin, Allison S. Thomas, Adam A. Capoferri, Subul A. Beg, Szu Han Huang, Sara Karandish, Haiping Hao, Eitan Halper-Stromberg, Patrick C. Yong, Colin Kovacs, Erika Benko, Robert F. Siliciano, Ya Chi Ho

Research output: Contribution to journalArticlepeer-review

Abstract

Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells, creating a barrier to cure. The majority of HIV-1 proviruses are defective and considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed into RNAs that are spliced and translated. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts, and cells with these proviruses can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Further, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs, potentially through aberrant translation. Thus, CTLs may change the landscape of HIV-1 proviruses by preferentially targeting cells with specific types of defective proviruses. Additionally, the expression of defective proviruses will need to be considered in the measurement of HIV-1 latency reversal.

Original languageEnglish (US)
Pages (from-to)494-506.e4
JournalCell Host and Microbe
Volume21
Issue number4
DOIs
StatePublished - Apr 12 2017

Keywords

  • APOBEC-mediated G-to-A hypermutations
  • HIV-1 cure
  • HIV-1 latent reservoir
  • HIV-1 proviral landscape
  • alternative splicing
  • cell-associated HIV-1 RNA
  • cold-target inhibition
  • cytotoxic T lymphocytes
  • defective HIV-1 proviruses
  • defective ribosomal product

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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