Control of the HIV-1 DNA reservoir is associated in vivo and in vitro with NKp46/NKp30 (CD335 CD337) inducibility and interferon gamma production by transcriptionally unique NK cells

Francesco Marras, Anna Casabianca, Federica Bozzano, Maria Libera Ascierto, Chiara Orlandi, Antonio Di Biagio, Emanuele Pontali, Chiara Dentone, Giancarlo Orofino, Laura Nicolini, Lucia Taramasso, Mauro Magnani, Francesco M. Marincola, Ena Wang, Lorenzo Moretta, Andrea De Maria

Research output: Contribution to journalArticle

Abstract

The size of lentiviral DNA reservoirs reflects the effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding the innate mechanisms contributing to containment of the HIV DNA reservoir, however, are only partly clarified and are relevant to guiding interventions for reservoir containment or eradication. We studied the contribution of natural killer (NK) cell functional features in HIV patients controlling replication either spontaneously (HIV controllers [HIC]) or after progression and antiretroviral treatment (progressor patients [PP]). An inverse correlation between HIV DNA copy numbers (either total or integrated) in circulating CD4+ cells and NK cell function was observed. Induced interferon gamma (IFN-γ) production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only for a homogeneous cohort of HIC patients but also when PP were included in the analysis. Adaptive (NKG2C+ CD57+) NK cell features were not associated with reservoir size. However, a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV DNA reservoir size. In proof-of-principle in vitro experiments of CD4+ cell infection with HIV-1, purified NK cells with the abovementioned functional/transcriptional features displayed 10- and 30-fold higher abilities to control HIV replication and DNA burdens in vitro, respectively, than those of other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of the HIV reservoir in CD4+ cells. Their selection, expansion, and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment.

Original languageEnglish
Article numbere00647-17
JournalJournal of Virology
Volume91
Issue number23
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • DNA
  • HIV-1
  • Interferons
  • Lentiviruses
  • Natural killer cells
  • Reservoir

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Marras, F., Casabianca, A., Bozzano, F., Ascierto, M. L., Orlandi, C., Di Biagio, A., Pontali, E., Dentone, C., Orofino, G., Nicolini, L., Taramasso, L., Magnani, M., Marincola, F. M., Wang, E., Moretta, L., & De Maria, A. (2017). Control of the HIV-1 DNA reservoir is associated in vivo and in vitro with NKp46/NKp30 (CD335 CD337) inducibility and interferon gamma production by transcriptionally unique NK cells. Journal of Virology, 91(23), [e00647-17]. https://doi.org/10.1128/JVI.00647-17