Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells

George N. Llewellyn, Eduardo Seclén, Stephen W Wietgrefe, Siyu Liu, Morgan Chateau, Hua Pei, Katherine Perkey, Matthew D. Marsden, Sarah J. Hinkley, David E. Paschon, Michael C. Holmes, Jerome A. Zack, Stan G. Louie, Ashley T Haase, Paula M. Cannona

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Combination anti-retroviral drug therapy (ART) potently suppresses HIV-1 replication but does not result in virus eradication or a cure. A major contributing factor is the long-term persistence of a reservoir of latently infected cells. To study this reservoir, we established a humanized mouse model of HIV-1 infection and ART suppression based on an oral ART regimen. Similar to humans, HIV-1 levels in the blood of ART-treated animals were frequently suppressed below the limits of detection. However, the limited timeframe of the mouse model and the small volume of available samples makes it a challenging model with which to achieve full viral suppression and to investigate the latent reservoir. We therefore used an ex vivo latency reactivation assay that allows a semiquantitative measure of the latent reservoir that establishes in individual animals, regardless of whether they are treated with ART. Using this assay, we found that latently infected human CD4 T cells can be readily detected in mouse lymphoid tissues and that latent HIV-1 was enriched in populations expressing markers of T cell exhaustion, PD-1 and TIGIT. In addition, we were able to use the ex vivo latency reactivation assay to demonstrate that HIV-specific TALENs can reduce the fraction of reactivatable virus in the latently infected cell population that establishes in vivo, supporting the use of targeted nuclease-based approaches for an HIV-1 cure. IMPORTANCE HIV-1 can establish latent infections that are not cleared by current antiretroviral drugs or the body’s immune responses and therefore represent a major barrier to curing HIV-infected individuals. However, the lack of expression of viral antigens on latently infected cells makes them difficult to identify or study. Here, we describe a humanized mouse model that can be used to detect latent but reactivatable HIV-1 in both untreated mice and those on ART and therefore provides a simple system with which to study the latent HIV-1 reservoir and the impact of interventions aimed at reducing it.

Original languageEnglish (US)
Article numbere02086-18
JournalJournal of virology
Volume93
Issue number10
DOIs
StatePublished - May 15 2019

Bibliographical note

Funding Information:
This study was supported by NIH grants AI110149 and HL129902 to P.M.C.

Keywords

  • HIV-1
  • Humanized mice
  • Latency
  • PD-1
  • TALEN
  • TIGIT

Fingerprint Dive into the research topics of 'Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1<sup>+</sup> and TIGIT<sup>+</sup> CD4 T cells'. Together they form a unique fingerprint.

Cite this