Essential Role of Human T Cell Leukemia Virus Type 1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice

Veronica Galli, Christopher C. Nixon, Natasa Strbo, Maria Artesi, Maria F. de Castro-Amarante, Katherine McKinnon, Dai Fujikawa, Maria Omsland, Robyn Washington-Parks, Laura Romero, Breanna Caruso, Keith Durkin, Sophia Brown, Baktiar Karim, Monica Vaccari, Steve Jacobson, Jerome A. Zack, Anne Van den Broeke, Cynthia Pise-Masison, Genoveffa Franchini

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is the ethological agent of adult T cell leukemia/lymphoma (ATLL) and a number of lymphocyte-mediated inflammatory conditions, including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 orf-I encodes two proteins, p8 and p12, whose functions in humans are to counteract innate and adaptive responses and to support viral transmission. However, the in vivo requirements for orf-I expression vary in different animal models. In macaques, the ablation of orf-I expression by mutation of its ATG initiation codon abolishes the infectivity of the molecular clone HTLV-1p12KO In rabbits, HTLV-1p12KO is infective and persists efficiently. We used humanized mouse models to assess the infectivity of both wild-type HTLV-1 (HTLV-1WT) and HTLV-1p12KO We found that NOD/SCID/γC-/- c-kit+ mice engrafted with human tissues 1 day after birth (designated NSG-1d mice) were highly susceptible to infection by HTLV-1WT, with a syndrome characterized by the rapid polyclonal proliferation and infiltration of CD4+ CD25+ T cells into vital organs, weight loss, and death. HTLV-1 clonality studies revealed the presence of multiple clones of low abundance, confirming the polyclonal expansion of HTLV-1-infected cells in vivo HTLV-1p12KO infection in a bone marrow-liver-thymus (BLT) mouse model prone to graft-versus-host disease occurred only following reversion of the orf-I initiation codon mutation within weeks after exposure and was associated with high levels of HTLV-1 DNA in blood and the expansion of CD4+ CD25+ T cells. Thus, the incomplete reconstitution of the human immune system in BLT mice may provide a window of opportunity for HTLV-1 replication and the selection of viral variants with greater fitness.IMPORTANCE Humanized mice constitute a useful model for studying the HTLV-1-associated polyclonal proliferation of CD4+ T cells and viral integration sites in the human genome. The rapid death of infected animals, however, appears to preclude the clonal selection typically observed in human ATLL, which normally develops in 2 to 5% of individuals infected with HTLV-1. Nevertheless, the expansion of multiple clones of low abundance in these humanized mice mirrors the early phase of HTLV-1 infection in humans, providing a useful model to investigate approaches to inhibit virus-induced CD4+ T cell proliferation.

Original languageEnglish (US)
JournalJournal of virology
Volume93
Issue number19
DOIs
StatePublished - Oct 1 2019
Externally publishedYes

Fingerprint

Deltaretrovirus
Contagious Ecthyma
lethal genes
Cell Proliferation
mice
T-lymphocytes
cells
Adult T Cell Leukemia Lymphoma
Deltaretrovirus Infections
T-Lymphocytes
start codon
Initiator Codon
Clone Cells
animal models
clones
lymphoma
leukemia
bone marrow
Thymus Gland
pathogenicity

Keywords

  • CD4+ CD25+
  • HTLV-1
  • humanized mouse models
  • orf-I
  • viral replication

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Essential Role of Human T Cell Leukemia Virus Type 1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice. / Galli, Veronica; Nixon, Christopher C.; Strbo, Natasa; Artesi, Maria; de Castro-Amarante, Maria F.; McKinnon, Katherine; Fujikawa, Dai; Omsland, Maria; Washington-Parks, Robyn; Romero, Laura; Caruso, Breanna; Durkin, Keith; Brown, Sophia; Karim, Baktiar; Vaccari, Monica; Jacobson, Steve; Zack, Jerome A.; Van den Broeke, Anne; Pise-Masison, Cynthia; Franchini, Genoveffa.

In: Journal of virology, Vol. 93, No. 19, 01.10.2019.

Research output: Contribution to journalArticle

Galli, V, Nixon, CC, Strbo, N, Artesi, M, de Castro-Amarante, MF, McKinnon, K, Fujikawa, D, Omsland, M, Washington-Parks, R, Romero, L, Caruso, B, Durkin, K, Brown, S, Karim, B, Vaccari, M, Jacobson, S, Zack, JA, Van den Broeke, A, Pise-Masison, C & Franchini, G 2019, 'Essential Role of Human T Cell Leukemia Virus Type 1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice', Journal of virology, vol. 93, no. 19. https://doi.org/10.1128/JVI.00565-19
Galli, Veronica ; Nixon, Christopher C. ; Strbo, Natasa ; Artesi, Maria ; de Castro-Amarante, Maria F. ; McKinnon, Katherine ; Fujikawa, Dai ; Omsland, Maria ; Washington-Parks, Robyn ; Romero, Laura ; Caruso, Breanna ; Durkin, Keith ; Brown, Sophia ; Karim, Baktiar ; Vaccari, Monica ; Jacobson, Steve ; Zack, Jerome A. ; Van den Broeke, Anne ; Pise-Masison, Cynthia ; Franchini, Genoveffa. / Essential Role of Human T Cell Leukemia Virus Type 1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice. In: Journal of virology. 2019 ; Vol. 93, No. 19.
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T1 - Essential Role of Human T Cell Leukemia Virus Type 1 orf-I in Lethal Proliferation of CD4+ Cells in Humanized Mice

AU - Galli, Veronica

AU - Nixon, Christopher C.

AU - Strbo, Natasa

AU - Artesi, Maria

AU - de Castro-Amarante, Maria F.

AU - McKinnon, Katherine

AU - Fujikawa, Dai

AU - Omsland, Maria

AU - Washington-Parks, Robyn

AU - Romero, Laura

AU - Caruso, Breanna

AU - Durkin, Keith

AU - Brown, Sophia

AU - Karim, Baktiar

AU - Vaccari, Monica

AU - Jacobson, Steve

AU - Zack, Jerome A.

AU - Van den Broeke, Anne

AU - Pise-Masison, Cynthia

AU - Franchini, Genoveffa

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Human T cell leukemia virus type 1 (HTLV-1) is the ethological agent of adult T cell leukemia/lymphoma (ATLL) and a number of lymphocyte-mediated inflammatory conditions, including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 orf-I encodes two proteins, p8 and p12, whose functions in humans are to counteract innate and adaptive responses and to support viral transmission. However, the in vivo requirements for orf-I expression vary in different animal models. In macaques, the ablation of orf-I expression by mutation of its ATG initiation codon abolishes the infectivity of the molecular clone HTLV-1p12KO In rabbits, HTLV-1p12KO is infective and persists efficiently. We used humanized mouse models to assess the infectivity of both wild-type HTLV-1 (HTLV-1WT) and HTLV-1p12KO We found that NOD/SCID/γC-/- c-kit+ mice engrafted with human tissues 1 day after birth (designated NSG-1d mice) were highly susceptible to infection by HTLV-1WT, with a syndrome characterized by the rapid polyclonal proliferation and infiltration of CD4+ CD25+ T cells into vital organs, weight loss, and death. HTLV-1 clonality studies revealed the presence of multiple clones of low abundance, confirming the polyclonal expansion of HTLV-1-infected cells in vivo HTLV-1p12KO infection in a bone marrow-liver-thymus (BLT) mouse model prone to graft-versus-host disease occurred only following reversion of the orf-I initiation codon mutation within weeks after exposure and was associated with high levels of HTLV-1 DNA in blood and the expansion of CD4+ CD25+ T cells. Thus, the incomplete reconstitution of the human immune system in BLT mice may provide a window of opportunity for HTLV-1 replication and the selection of viral variants with greater fitness.IMPORTANCE Humanized mice constitute a useful model for studying the HTLV-1-associated polyclonal proliferation of CD4+ T cells and viral integration sites in the human genome. The rapid death of infected animals, however, appears to preclude the clonal selection typically observed in human ATLL, which normally develops in 2 to 5% of individuals infected with HTLV-1. Nevertheless, the expansion of multiple clones of low abundance in these humanized mice mirrors the early phase of HTLV-1 infection in humans, providing a useful model to investigate approaches to inhibit virus-induced CD4+ T cell proliferation.

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KW - HTLV-1

KW - humanized mouse models

KW - orf-I

KW - viral replication

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