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Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model.

ABSTRACT: A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation. Said model will enable in vivo mechanistic studies, thus complementing the well-established surrogate model of SIV infection-induced lymphoid tissue fibrosis in macaques. We developed a potentially novel human immune system-humanized mouse model by coengrafting autologous fetal thymus, spleen, and liver organoids under the kidney capsule, along with i.v. injection of autologous fetal liver-derived hematopoietic stem cells, thus termed the BM-liver-thymus-spleen (BLTS) humanized mouse model. BLTS humanized mouse model supports development of human immune cells and human lymphoid organoids (human thymus and spleen organoids). HIV infection in BLTS humanized mice results in progressive fibrosis in human lymphoid tissues, which was associated with immunodeficiency in the lymphoid tissues, and lymphoid tissue fibrosis persists during ART, thus recapitulating clinical outcomes.

SUBMITTER: Samal J

PROVIDER: S-EPMC6237217 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model.

Samal Jasmine J Kelly Samantha S Na-Shatal Ali A Elhakiem Abdallah A Das Antu A Ding Ming M Sanyal Anwesha A Gupta Phalguni P Melody Kevin K Roland Brad B Ahmed Watfa W Zakir Aala A Bility Moses M

JCI insight 20180920 18

A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency ...[more]

PMID: 30232273

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Project description:BackgroundThe accurate assessment of liver fibrosis is essential for patients with chronic liver disease. A liver biopsy is an invasive procedure that has many potential defects and complications. Therefore, noninvasive assessment techniques are of considerable value for clinical diagnosis. Liver and spleen magnetic resonance elastography (MRE) and serum markers have been proposed for quantitative and noninvasive assessment of liver fibrosis. This study aims to compare the diagnostic performance of liver and spleen stiffness measured by MRE, fibrosis index based on the 4 factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and their combined models for staging hepatic fibrosis.MethodsOne hundred and twenty patients with chronic liver disease underwent MRE scans. Liver and spleen stiffness were measured by the MRE stiffness maps. Serum markers were collected to calculate FIB-4 and APRI. Liver biopsies were used to identify pathologic grading. Spearman’s rank correlation analysis evaluated the correlation between the parameters and fibrosis stages. Receiver operating characteristic (ROC) analysis evaluated the performance of the four individual parameters, a liver and spleen stiffness combined model, and an all-parameters combined model in assessing liver fibrosis.ResultsLiver stiffness, spleen stiffness, FIB-4, and APRI were all correlated with fibrosis stage (r=0.87, 0.64, 0.65, and 0.51, respectively, all P<0.001). Among the 4 individual diagnostic markers, liver stiffness showed the highest values in staging F1–4, F2–4, F3–4 and F4 (AUC =0.89, 0. 97, 0.95, and 0.95, all P<0.001). The AUCs of the liver and spleen stiffness combined model in the F1–4, F2–4, F3–4, and F4 staging groups were 0.89, 0.97, 0.95, and 0.96, respectively (all P<0.001). The corresponding AUCs of the all-parameters combined model were 0.90, 0.97, 0.95, and 0.96 (all P<0.001). The AUCs of the liver and spleen stiffness combined model were significantly higher than those of APRI, FIB-4 in the F2–4, F3–4, and F4 staging groups (all P<0.05). Both combined models were not significantly different from liver stiffness in staging liver fibrosis (all P>0.05).ConclusionsLiver stiffness measured with MRE had better diagnostic performance than spleen stiffness, APRI, and FIB-4 for fibrosis staging. The combined models did not significantly improve the diagnostic value compared with liver stiffness in staging fibrosis.

Project description:Humanized mice are emerging as an alternative model system to well-established non-human primate (NHP) models for studying human immunodeficiency virus (HIV)-1 biology and pathogenesis. Although both NHP and humanized mice have their own strengths and could never truly reflect the complex human immune system and biology, there are several advantages of using the humanized mice in terms of using primary HIV-1 for infection instead of simian immunodeficiency virus or chimera simian/HIV. Several different types of humanized mice have been developed with varying levels of reconstitution of human CD45+ cells. In this study, we utilized humanized Rag1KO.IL2R?cKO.NOD mice expressing HLA class II (DR4) molecule (DRAG mice) infused with HLA-matched hematopoietic stem cells from umbilical cord blood to study early events after HIV-1 infection, since the mucosal tissues of these mice are highly enriched for human lymphocytes and express the receptors and coreceptors needed for HIV-1 entry. We examined the various tissues on days 4, 7, 14, and 21 after an intravaginal administration of a single dose of purified primary HIV-1. Plasma HIV-1 RNA was detected as early as day 7, with 100% of the animals becoming plasma RNA positive by day 21 post-infection. Single cells were isolated from lymph nodes, bone marrow, spleen, gut, female reproductive tissue, and brain and analyzed for gag RNA and strong stop DNA by quantitative (RT)-PCR. Our data demonstrated the presence of HIV-1 viral RNA and DNA in all of the tissues examined and that the virus was replication competent and spread rapidly. Bone marrow, gut, and lymph nodes were viral RNA positive by day 4 post-infection, while other tissues and plasma became positive typically between 7 and 14?days post-infection. Interestingly, the brain was the last tissue to become HIV-1 viral RNA and DNA positive by day 21 post-infection. These data support the notion that humanized DRAG mice could serve as an excellent model for studying the trafficking of HIV-1 to the various tissues, identification of cells harboring the virus, and thus could serve as a model system for HIV-1 pathogenesis and reservoir studies.

Project description:BACKGROUND:A recent retrospective study confirmed that hepatic stiffness and splenic stiffness measured with magnetic resonance elastography (MRE) are strongly associated with the presence of esophageal varices. In addition, strong correlations have been reported between splenic stiffness values measured with MRE and hepatic venous pressure gradients in animal models. However, most studies have been conducted on adult populations, and previous pediatric MRE studies have only demonstrated the feasibility of MRE in pediatric populations, while the actual clinical application of spleen MRE has been limited. AIM:To assess the utility of splenic stiffness measurements by MRE to predict gastroesophageal varices in children. METHODS:We retrospectively reviewed abdominal MRE images taken on a 3T system in pediatric patients. Patients who had undergone Kasai operations for biliary atresia were selected for the Kasai group, and patients with normal livers and spleens were selected for the control group. Two-dimensional spin-echo echo-planar MRE acquisition centered on the liver, with a pneumatic driver at 60 Hz and a low amplitude, was performed to obtain hepatic and splenic stiffness values. Laboratory results for aspartate aminotransferase to platelet ratio index (APRI) were evaluated within six months of MRE, and the normalized spleen size ratio was determined with the upper normal size limit. All Kasai group patients underwent gastroesophageal endoscopy during routine follow-up. The Mann-Whitney U test, Kendall's tau b correlation and diagnostic performance analysis using the area under the curve (AUC) were performed for statistical analysis. RESULTS:The median spleen MRE value was 5.5 kPa in the control group (n = 9, age 9-18 years, range 4.7-6.4 kPa) and 8.6 kPa in the Kasai group (n = 22, age 4-18 years, range 5.0-17.8 kPa). In the Kasai group, the APRI, spleen size ratio and spleen MRE values were higher in patients with portal hypertension (n = 11) than in patients without (n = 11) (all P < 0.001) and in patients with gastroesophageal varices (n = 6) than in patients without (n = 16) (all P < 0.05), even though their liver MRE values were not different. The APRI (? = 0.477, P = 0.007), spleen size ratio (? = 0.401, P = 0.024) and spleen MRE values (? = 0.426, P = 0.016) also correlated with varices grades. The AUC in predicting gastroesophageal varices was 0.844 at a cut-off of 0.65 (100% sensitivity and 75% specificity) for the APRI, and 0.844 at a cut-off of 9.9 kPa (83.3% sensitivity and 81.3% specificity) for spleen MRE values. CONCLUSION:At a cut-off of 9.9 kPa, spleen MRE values predicted gastroesophageal varices as well as the APRI and spleen size ratio in biliary atresia patients after the Kasai operation. However, liver MRE values were not useful for this purpose.

Dataset Information

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model.

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Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model.

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