HIV-1 cellular and tissue replication patterns in infected humanized mice

Abstract

Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Cells were analyzed by flow cytometry and sorted from species mixtures defined as CD34+ lineage negative progenitor cells, CD14+CD16+ monocyte-macrophages and central, stem cell and effector memory T cells. The cell distribution and viral life cycle were found dependent on the tissue compartment and time of infection. Cell subsets contained HIV-1 total and integrated DNA as well as multi-spliced and unspliced RNA in divergent proportions. The data support the idea that humanized mice can provide a means to examine the multifaceted sites of HIV-1 replication including, but not limited to progenitor cells and monocyte-macrophages previously possible only in macaques and human.

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

“…This is most likely explained by a T CM population capable of continuous high-level production of new T EM (46). Comparing the T cell population in the acute versus chronic phases of HIV infection, we observed a prominent contraction of CD4 + T N , whereas the T EM population expanded, in the chronic phase; the contraction/expansion of CD4 + T cell subsets that we observed was similar to that observed in HIV-infected NSG mice (30). Notably, the distribution of splenic T cell subsets in uninfected MISTRG mice resembled that of reconstituted NSG mice (47) and of healthy humans (48).…”

“…Most HIV studies in hu mice were done with humanized Rag2 2/2 gc 2/2 (26,27), NOG (28), or NSG (29) mice. Hu mice have been used to study HIV pathogenesis (30)(31)(32) and to explore novel therapeutic modalities (33,34), including gene engineering of an HIV-resistant immune system (35,36). Naturally, HIV research benefits from the ongoing efforts to improve humanization in mice.…”

Humanized Mice as Unique Tools for Human-Specific Studies

“…A particular human-specific infectious pathogen that has been successfully studied on humanized mice is a retrovirus known as human immunodeficiency virus (HIV) (Araínga et al 2016; Berges and Rowan 2011; Choudhary et al 2009; Duyne et al 2011; Li et al 2014). Before humanized mice were introduced, the only non-human animal model available for dissecting HIV pathogenesis was the chimpanzee (Vanden Haesevelde et al 1996).…”

“…Chronic infection was asymptomatic and resulted in the development of hAdV-specific adaptive immunity and expression of early viral genes within the BMRodríguez et al (2017)hCMVNRG mice engrafted with CD34 + human cells isolated from adult PBMCs and UBC and infected with hCMVWhen a tricistronic integrase-defective lentiviral vector (co-expressing GM-CSF, IFN-α, and hCMV pp65 antigen) which induced self-differentiation of monocytes in PBMCs and UCB into DCs with pp65 (“SmyleDCpp65”) was administered, humanized mice infected with hCMV demonstrated remodeling of LNs, upregulation of thymopoiesis in CD4 + and CD8 + T cell precursors, polyclonal effector memory CD8 + T cells expansion in blood, spleen, and BM, PP65-specific CTL, and IgG responsesDaenthanasanmak et al (2015)HIVNewborn NSG intrahepatically injected with CD34 + human FL cells and infected with HIV-1 ADA via intraperitoneal injectionCell distribution and HIV viral life cycle were dependent on tissue compartment and time of infection. HIV-1 in cells was found as forms of integrated DNA and multi- and un-spliced RNAAraínga et al (2016)HTLV1NOG mice engrafted with human CD133 + UBC cells by IBMI) to create IBMI-huNOG mice which were intraperitoneally infected with HTLV-1Infected mice recapitulated symptoms of adult T-cell leukemia and HTLV-1-specific adaptive immune responses including, elevation of CD4 + T cells, and signs of atypical lymphocytes with lobulated nucleiTezuka et al (2014)InfluenzaRag2 −/− γc −/−  mice intraperitoneally injected with human PBMCs and Intranasally infected with InfluenzaIntraperitoneal injection of pamidronate induced Vδ2-T cells to secrete IFN-γ and kill virus infected host cells which helped to control viral replication and suppressed inflammation in lungs of H7N9-infected mice, reducing their morbidity and mortalityZheng et al (2015)KSHVNSG mice engrafted with human fetal thymus and liver tissue under the kidney capsule and intravenously injected with CD34 + human FL cells to create huBLT mice. Mice were infected with KSHV via the oral mucosaMice were infected with KSHV via the oral mucosa and established a robust infection by targeting human macrophages and B cellsWang et al (2014)Leishmania majorNewborn NSG intrahepatically injected with human CD34 + UBC cells and infected with Leishmania major via subcutaneous footpad injectionAt the site of injection, human macrophages were infected with Leishmania parasites and Leishmania -specific human T cell responses were detected.…”

A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy

“…The HIV-1 infected humanized NSG mice can mimic critical features of human disease and are suitable to explore antiretroviral and adjunctive therapies [10–13, 40]. Noteworthy limitations include the life span of the human grafts and the human cell recovery rates.…”