Diverse effects of interferon alpha on the establishment and reversal of HIV latency

PLoS Pathog. 2020 Feb 28;16(2):e1008151. doi: 10.1371/journal.ppat.1008151. eCollection 2020 Feb.

Abstract

HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4+ T cells. Latently infected CD4+ T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4+ T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFNα, IFNβ and IFNω but not IFNε or type III IFNλ1 and IFNλ3. However, once latency was established, IFNα but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4+ T cells collected from PLWH on suppressive ART. Binding of IFNα to its receptor expressed on primary CD4+ T cells did not induce activation of the canonical or non-canonical NFκB pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFNα; inhibiting the establishment of latency but also reversing HIV latency once latency is established.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / pathology
  • CD4-Positive T-Lymphocytes* / virology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Dendritic Cells / virology
  • HEK293 Cells
  • HIV Long Terminal Repeat / immunology*
  • HIV-1 / physiology*
  • Humans
  • Interferon-alpha / immunology*
  • NF-kappa B / immunology
  • STAT Transcription Factors / immunology
  • Transcription, Genetic / immunology*
  • Virus Latency / immunology*

Substances

  • Interferon-alpha
  • NF-kappa B
  • STAT Transcription Factors

Grants and funding

This work was supported by the Australian National Health and Medical Research Council (NHMRC) Project Grant 1041795 and 3162044, S.R.L. is an NHMRC practitioner fellow, R.M.S is a AIAS-COFUND II (Marie Curie) Junior Fellow (grant no A7873), the scheme is funded by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie actions (grant agreement no 754513) and Aarhus University Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript