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 journalArticle

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 1 2019

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Human immunodeficiency virus 1
HIV-1
T-lymphocytes
animal models
drug therapy
Viruses
T-Lymphocytes
viruses
Drug Therapy
assays
HIV
Viral Antigens
nucleases
viral antigens
mice
Lymphoid Tissue
cells
antiretroviral agents
infection
Population

Keywords

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

PubMed: MeSH publication types

  • Journal Article

Cite this

Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells. / Llewellyn, George N.; Seclén, Eduardo; Wietgrefe, Stephen W; Liu, Siyu; Chateau, Morgan; Pei, Hua; Perkey, Katherine; Marsden, Matthew D.; Hinkley, Sarah J.; Paschon, David E.; Holmes, Michael C.; Zack, Jerome A.; Louie, Stan G.; Haase, Ashley T; Cannona, Paula M.

In: Journal of virology, Vol. 93, No. 10, e02086-18, 01.05.2019.

Research output: Contribution to journalArticle

Llewellyn, GN, Seclén, E, Wietgrefe, SW, Liu, S, Chateau, M, Pei, H, Perkey, K, Marsden, MD, Hinkley, SJ, Paschon, DE, Holmes, MC, Zack, JA, Louie, SG, Haase, AT & Cannona, PM 2019, 'Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells', Journal of virology, vol. 93, no. 10, e02086-18. https://doi.org/10.1128/JVI.02086-18
Llewellyn, George N. ; Seclén, Eduardo ; Wietgrefe, Stephen W ; Liu, Siyu ; Chateau, Morgan ; Pei, Hua ; Perkey, Katherine ; Marsden, Matthew D. ; Hinkley, Sarah J. ; Paschon, David E. ; Holmes, Michael C. ; Zack, Jerome A. ; Louie, Stan G. ; Haase, Ashley T ; Cannona, Paula M. / Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells. In: Journal of virology. 2019 ; Vol. 93, No. 10.
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