Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Saumi Mathews, Amanda Branch Woods, Ikumi Katano, Edward Makarov, Midhun B. Thomas, Howard Eliot Gendelman, Larisa Y Poluektova, Mamoru Ito, Santhi Gorantla

Research output: Contribution to journalArticle

Abstract

Background: Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell's presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain. Once infected, however, microglia become immune competent serving as sources of cellular neurotoxic factors leading to disrupted brain homeostasis and neurodegeneration. Methods: Herein, we created a humanized bone-marrow chimera producing human "microglia like" cells in NOD.Cg-Prkdc scid Il2rg tm1Sug Tg(CMV-IL34)1/Jic mice. Newborn mice were engrafted intrahepatically with umbilical cord blood derived CD34+ hematopoietic stem progenitor cells (HSPC). After 3 months of stable engraftment, animals were infected with HIV-1ADA, a myeloid-specific tropic viral isolate. Virologic, immune and brain immunohistology were performed on blood, peripheral lymphoid tissues, and brain. Results: Human interleukin-34 under the control of the cytomegalovirus promoter inserted in NSG mouse strain drove brain reconstitution of HSPC derived peripheral macrophages into microglial-like cells. These human cells expressed canonical human microglial cell markers that included CD14, CD68, CD163, CD11b, ITGB2, CX3CR1, CSFR1, TREM2 and P2RY12. Prior restriction to HIV-1 infection in the rodent brain rested on an inability to reconstitute human microglia. Thus, the natural emergence of these cells from ingressed peripheral macrophages to the brain could allow, for the first time, the study of a CNS viral reservoir. To this end we monitored HIV-1 infection in a rodent brain. Viral RNA and HIV-1p24 antigens were readily observed in infected brain tissues. Deep RNA sequencing of these infected mice and differential expression analysis revealed human-specific molecular signatures representative of antiviral and neuroinflammatory responses. Conclusions: This humanized microglia mouse reflected human HIV-1 infection in its known principal reservoir and showed the development of disease-specific innate immune inflammatory and neurotoxic responses mirroring what can occur in an infected human brain.

Original languageEnglish (US)
Article number12
JournalMolecular Neurodegeneration
Volume14
Issue number1
DOIs
StatePublished - Mar 5 2019

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Microglia
HIV Infections
HIV-1
Cell Differentiation
Brain
Hematopoietic Stem Cells
Macrophages
Nervous System
human interleukin-34
Rodentia
HIV Antigens
HIV
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
Time and Motion Studies
Viral RNA
Lymphoid Tissue
Virus Diseases
Cytomegalovirus
Fetal Blood

Keywords

  • HIV-1 infection
  • Hematopoietic stem cells
  • Humanized mice
  • Microglia

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice. / Mathews, Saumi; Branch Woods, Amanda; Katano, Ikumi; Makarov, Edward; Thomas, Midhun B.; Gendelman, Howard Eliot; Poluektova, Larisa Y; Ito, Mamoru; Gorantla, Santhi.

In: Molecular Neurodegeneration, Vol. 14, No. 1, 12, 05.03.2019.

Research output: Contribution to journalArticle

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AU - Katano, Ikumi

AU - Makarov, Edward

AU - Thomas, Midhun B.

AU - Gendelman, Howard Eliot

AU - Poluektova, Larisa Y

AU - Ito, Mamoru

AU - Gorantla, Santhi

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