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

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-1 ADA , 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.

Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

“…Recently, using a humanized mouse model, macrophages were shown to sustain HIV-1 infection and replication, even in the absence of T cells (Honeycutt et al, 2017;Honeycutt et al, 2016). This is in line with several studies characterizing tissue macrophages, such as alveolar, microglia and gut macrophages, as reservoirs in HIV-1 patients undergoing antiretroviral therapy (Ganor et al, 2019;Jambo et al, 2014;Mathews et al, 2019;Sattentau and Stevenson, 2016). Macrophages are key host cells for Mtb (O'Garra et al, 2013;VanderVen et al, 2016).…”

Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

“…Recently, using a humanized mouse model, macrophages were shown to sustain HIV-1 infection and replication, even in the absence of T cells (Honeycutt et al, 2017;Honeycutt et al, 2016). This is in line with several studies characterizing tissue macrophages, such as alveolar, microglia and gut macrophages, as reservoirs in HIV-1 patients undergoing antiretroviral therapy (Ganor et al, 2019;Jambo et al, 2014;Mathews et al, 2019;Sattentau and Stevenson, 2016).…”

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…In certain virus infections of the CNS, such as for instance in HIV infections, microglia are by themselves infected and propagate the infection in the brain and spinal cord (Burdo, Lackner, & Williams, 2013). As an example, "humanized" bone marrow chimeric mice are susceptible to brain infection by HIV, when the transplanted cells develop into cells with microglia properties within the CNS (Mathews et al, 2019). In addition, as shown by single cell gene expression analysis, chronic microglia infection in the AIDS brain may result in their functional impairment and senescence, which may impair their homeostatic function in chronic brain inflammation (Chen, Partridge, Sell, Torres, & Martin-Garcia, 2017;Ginsberg et al, 2018).…”