
==== Front
Animal Model Exp Med
Animal Model Exp Med
10.1002/(ISSN)2576-2095
AME2
Animal Models and Experimental Medicine
2096-5451
2576-2095
John Wiley and Sons Inc. Hoboken

38567763
10.1002/ame2.12409
AME212409
AMEM-2023-0108.R1
Review
Regular Article
Review
How can we establish animal models of HIV‐associated lymphoma?
Xiao et al.
Xiao Qing 1
Zhai Liuyue 1
Zhang Xiaomei 1
Liu Yi 1
Li Jun 1
Xie Xiaoqing 1
Xu Guofa 1
He Sanxiu 1
Fu Huihui 1
Tang Yifeng 1
Zhang Fujie 2 treatment@chinaaids.cn

Liu Yao https://orcid.org/0000-0003-1782-7322
1 liuyao77@cqu.edu.cn

1 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology‐Oncology Chongqing University Cancer Hospital Chongqing China
2 Beijing Ditan Hospital Capital Medical University Beijing China
* Correspondence
Fujie Zhang, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
Email: treatment@chinaaids.cn
Yao Liu, Department of Hematology‐Oncology, Chongqing University Cancer Hospital, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing 400030, China.
Email: liuyao77@cqu.edu.cn

03 4 2024
8 2024
7 4 10.1002/ame2.v7.4 Themed Issue: Study on Cardiovascular and Cerebrovascular Diseases 484496
21 9 2023
27 2 2024
© 2024 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV‐associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

animal model
HIV‐associated lymphoma (HAL)
human immunodeficiency virus (HIV)
immunodeficient mice
primate model
Chongqing Professional Talents Plancstc2022ycjh‐bgzxm0048 Fundamental Research Funds for the Central Universities 10.13039/501100012226 2022CDJYGRH‐001 Natural Science Foundation of Chongqing, China 10.13039/501100005230 CSTB2022NSCQ‐MSX1150 source-schema-version-number2.0
cover-dateAugust 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:03.09.2024
Xiao Q , Zhai L , Zhang X , et al. How can we establish animal models of HIV‐associated lymphoma? Anim Models Exp Med. 2024;7 :484‐496. doi:10.1002/ame2.12409

Qing Xiao and Liuyue Zhai contributed equally to this work.
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pmc1 INTRODUCTION

Human immunodeficiency virus (HIV) infection significantly raises the risk of several cancers, encompassing acquired immunodeficiency syndrome (AIDS)‐defining cancers and non‐AIDS‐defining cancers. 1 Among these, AIDS‐defining cancers include Kaposi sarcoma (KS), non‐Hodgkin lymphoma (NHL) and invasive cervical carcinoma. The AIDS‐defined NHL category includes primary central nervous system lymphoma (PCNSL), Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), plasmoblastic lymphoma (PBL), and primary effusion lymphoma (PEL). 2 DLBCL, BL, PBL, PCNSL, and PEL are high‐grade B cell lymphomas, with DLBCL and BL together accounting for over 60% of HIV‐associated lymphomas (HALs). 3 , 4

The subtypes and pathogenesis of lymphomas in people living with HIV (PLWH) diverge from those observed in the immunocompetent population. Lymphomas in PLWH tend to manifest at more advanced stages, progress more rapidly, entail more B‐symptoms, and more frequently affect extracolonic sites and the central nervous system compared to the general population. 5 , 6 The introduction of antiretroviral therapy (ART) has greatly reduced the risk of lymphomas and other AIDS‐defining cancers. 7 Regrettably, while lymphoma survival rates have notably improved in recent decades, overall survival for PLWH remains lower than that of the general population. 8 In the US and Europe, the overall risk of advanced NHL in the ART era is 10–20 times higher than that in the general population, with BL and PCNSL being particularly pronounced. 9 , 10 , 11

The intricate mechanisms underpinning the development of fatal HALs remain incompletely elucidated, although they are believed to involve impaired cellular immunity, loss of control over oncogenic viruses and chronic B cell activation. 12 , 13 Despite the multiplicity of etiological factors, effective experimental animal models that faithfully replicate human pathophysiology are currently lacking. Enhancing our understanding through current and future models will enable clinicians to manage and cure these malignancies more effectively. This review aims to provide an overview of existing animal models that could be potentially be used for studying HALs, thereby laying essential groundwork for addressing this substantial challenge.

2 MOUSE MODELS FOR HAL

Mouse models are widely used due to their rapid generation time, the abundance of commercial reagents, and the availability of transgenic mice. 14 There are numerous types of mouse models, including syngeneic models, genetically engineered mouse models, cell line‐derived xenograft (CDX) models, and patient‐derived (PDX) models. 15

2.1 Transgenic mice

Various HIV transgenic mouse lines have been developed to mimic AIDS‐like pathology. 16 , 17 , 18 , 19 , 20 Among them, the HIV Tg mouse line Tg26 has a 7.4‐kb pNL4‐3 HIV‐1 provirus with a 3.1‐kb sequence deletion in the gag‐pol region, rendering the virus non‐infectious. Approximately 15% of these HIV Tg mice spontaneously developed lymphomas, mirroring human HALs. The Tg lymphomas were preceded by diffuse lymphadenopathy and elevated proinflammatory serum cytokines. The transformed B cell population consists of clonal CD19+pre‐BCR+CD127+CD43+CD93+ precursor B cells. Loss of peripheral B cell subsets and infiltration of lymphoid organs by polyclonal B cells are hallmarks of the development of lymphoma in HIV Tg mice. 21 Tg26 mice are classified into three distinct disease phenotypes: asymptomatic, defined by the absence of cutaneous papillomas; early‐stage lymphomas, defined by splenomegaly associated with one enlarged lymph node; and lymphomas, characterized by systemic lymphadenopathy and circulating lymphoblastoid cells. 21 The HIV Tg26 mouse model allows the characterization of various stages of disease progression, potentially serving as a valuable model for HALs and for elucidating the potential role of HIV in B cell transformation. Transgenic mice do possess advantages, including the relative ease of generating mouse strains and potentially higher levels of transgene expression due to the availability of multiple copies. 22 However, transgenes with a high copy number insertion are more prone to epigenetic silencing, leading to decreased transgene expressions in successive generations. 23 Therefore, the stability of Tg26 mice remains to be thoroughly investigated. In addition, Tg26 mouse model does not completely mimic HIV infection in humans and has a low tumorigenicity rate, so its use is not widespread (Figure 1).

FIGURE 1 Schematic illustration of gene defects in Tg26 transgenic mice.

2.2 Immunodeficient xenograft mouse model

Xenotransplantation into immunodeficient mouse hosts serves as the standard approach for investigating human tissues in vivo. 24 To prevent rejection, immune‐deficient mice are employed in xenogeneic transplantation, a procedure involving the administration of cells from various donor species into mice. 25 The PDX model involves the creation of an animal xenograft model within severe combined immunodeficiency (SCID) mice using freshly resected or biopsied tumor tissues. This model effectively retains the original tumor tissue. 26 It can preserve cell–cell interactions and the tumor microenvironment, as well as the structural and stromal components of the primary tumor. However, PDX grafts have low success rates, long culture cycles, and high costs. An alternative model, the CDX model, entails the transplantation of human cancer cells from cell cultures into immunodeficient mice. 27 The CDX model is much easier to establish and maintain, and the transplantation success rate is high. However, the accumulation of genetic aberrations in cancer cell lines increases with passage number, and the lack of tumor heterogeneity highlights the limitations of cell line‐based models. 28

2.2.1 Immunodeficient mouse species

Numerous types of immunodeficient mice were used to construct PDX and CDX models of HALs, and these mice each have a different type of immunodeficiency (Table 1). SCID mice were discovered to possess genetic defects that prevent the functional development of T and B lymphocytes, enabling successful engraftment of a variety of normal hematopoietic and tumor cells. 32 , 44 , 45 , 46 The NOD‐SCID (NOD/LzSzPrkdc(SCID)/J) mouse strain is notably deficient in B and T lymphocytes, yet maintains natural killer (NK) cell activity, macrophage function, complement activity, and functional dendritic cells. 33 , 47 , 48 The NOD‐SCID strain appears to be more promising as a tool for human tumor xenografts than conventional SCID models. Mice derived from NOD‐SCID include T, B and NK‐cell knock‐out NOD/SCID/γcnull mice (NOG) and NOD/Scid/Jak3‐deficient mice (NOJ) have been used, alongside immunocompromised strains on the BALB/c background, like BRG and BRJ. These mice show complete deficiency not only of mature T/B lymphocytes and complement proteins, but also of NK cells. 47 , 49 , 50

TABLE 1 Types of immunodeficient mice.

Name of mice	Full name	Lack of functionality	References	
NMRI nude mice	Navy Medical Research Institute Nude Mouse	Lack of mature T cells	[29]	
NOD	non‐obese diabetic mice	Lack of regulatory T cells (Treg cells) and NK cells	[30, 31]	
SCID	severe combined immunodeficiency mice	Lack of functional T and B lymphocyte function	[32]	
NOD/SCID	NOD.CB17‐PrkdcScid/J Mice	Complete deficiency of mature T and B lymphocytes and complement proteins, and partial deficiency of NK cell, macrophage and dendritic cell function	[33, 34]	
C.B‐17‐SCID	C.B‐17 severe combined immunodeficiency mice	Lack of mature T and B cells	[32]	
C.B‐17 SCID‐Beige	C.B‐17 severe combined immunodeficiency beige mice	Lack of mature T and B cells, NK cells, Macrophage granzymes	[35]	
NRJ	NOD/Rag‐2/Jak3 double‐deficient mice	Complete lack of T/B lymphocytes and complement proteins, complete lack of NK cells	[36]	
NOJ	NOD‐/SCID‐/Jak3‐ mice	Multiple immune dysfunctions, including cytokine production capacity, in addition to T, B and NK cell dysfunction	[37, 38]	
NOG	NOD/SCID/gcnull mice	Complete lack of T, B, NK cells	[37, 38, 39]	
RJ	Rag‐2/Jak3 double deficient (Rag‐2−/−Jak3−/−) mice	Lack of mature T and B lymphocytes and NK cells	[40, 41]	
BRJ	Balb/c Rag‐2/Jak3 double deficient	Lack of T and B lymphocytes and NK cells	[42]	
Nude‐RJ mice	Balb/c nude Rag‐2(−/−)Jak3(−/−) mice	Lack of T and B lymphocytes or NK cells	[43]	

Certain mice with severe combined immunodeficiency are generated through crossbreeding different types of immunodeficient mice. For example, NOJ mice were established by crossing Jak3‐deficient mice with the NOD.Cg.‐Prkdcscid strain for ten generations. 51 NRJ mice were established by mating NOD Rag‐2 (−/−) mice with NOD Jak3 (−/−) mice. 36 NOD Rag‐2 (−/−) mice and NOD Jak3 (−/−) mice were established by breeding Rag‐2 (−/−) mice or Jak3 (−/−) mice, respectively, with the NOD strain for ten generations. 52 Balb/c Rag‐2 deficient (Rag‐2(−/−)) mice and Balb/c Jak3‐deficient (Jak3(−/−)) mice were established by crossing Rag‐2(−/−) mice 40 or Jak3(−/−) mice, respectively, 51 with the Balb/c strain for ten generations. Balb/c Rag‐2‐deficient (Rag‐2(−/−)) mice were crossed with Balb/c Jak‐3‐deficient (Jak3(−/−)) mice to establish BRJ mice. 42 , 53 These mice lacked mature T and B lymphocytes as well as NK cells, displaying high efficiency for human CD34+ hematopoietic stem cell (HSC) and peripheral blood mononuclear cell (PBMC) transplantation, along with human tumor xenografts. 42 Subsequently, Balb/c Nude Rag‐2(−/−)Jak3(−/−) (Nude‐RJ) mice were established by crossing Balb/c Rag‐2(−/−)Jak3(−/−) mice with Balb/c Nude mice. 43

2.2.2 HAL cell lines for establishing cell line‐derived xenograft mouse models

Tumor tissue was employed for generating xenografts and cell lines, 54 and a variety of cell lines of HALs have been reported before (Table 2). The R cell line was isolated in Dr Zaki Salahuddin's laboratory from tumor biopsy specimens obtained from AIDS patients with aggressive post‐treatment lymphoma. Displaying an immunoblast phenotype, this cell line is Epstein–Barr virus (EBV) positive and HIV‐negative. 55 Valerie L. Ng et al. obtained lymph node tissue from an AIDS‐associated Burkitt lymphoma (AIDS‐BL) patient. The tissue was shredded and filtered to prepare a single‐cell suspension, and then the cells were inoculated into culture flasks at a density of 2 × 106 /mL, with 50% of the culture medium replenished weekly. Over the following year, fetal bovine serum (FBS) gradually replaced human serum, and at the end of the year, cells were passaged every 3–4 days at a dilution of 1:10. The resulting cell line was named 2F7. 56 The ability of individual subclones to metastasize to the CNS was tested by labelling these 2F7 cells with the mStrawberry reporter gene using a lentiviral vector. Within seven weeks of intraperitoneal (i.p.) injection into mice, two‐tenths of the sublines formed CNS lymphomas. From one of these sublines, lymphoma cells were isolated from the brain and reintroduced to cell culture, resulting in the ‘2F7‐BR44’ cell line, which was positive for EBV. 57 JB cells were derived from microvascular endothelial cell stroma cultures of AIDS patients with BL, leading to spontaneous and sustained growth of BL cells. Most AIDS‐NHL cell lines are positive for EBV. The JB cell line is notable for being an EBV‐negative BL cell line, allowing the study of AIDS‐NHL in the absence of EBV infection. 58 Hiroki Goto established a novel PEL cell line, GTO, from the pericardial effusion of a 39‐year‐old Japanese patient with AIDS‐PEL. The line was latently infected with Kaposi sarcoma‐associated herpesvirus/human herpesvirus‐8 (KSHV, HHV‐8) but not with EBV. Lymphoma cells from the pericardial effusion were collected and cultivated in RPMI‐1640 supplemented with 20% heat‐inactivated FBS, 10% filtered pericardial effusion supernatant, penicillin, and streptomycin. Over passages, pericardial fluid supplementation and FBS concentration were gradually reduced until the cells were able to thrive without pericardial fluid. For long‐term culture, the cell line was maintained in RPMI‐1640 supplemented with 10% FBS. 59 The JSC‐1 cell line originated from the ascites of a 52‐year‐old homosexual male with HIV, presenting a lymphomatous peritoneal effusion without a discernible tumor mass, and no prior history of Kaposi's sarcoma or other malignancies. 63 BCBL‐1, another cell line, was established from an AIDS‐PEL patient. The lymphoma cells were cultured in RPMI‐1640 supplemented with 20% autologous ascites, 50 μg/mL gentamycin, 0.05 mM 2‐mercaptoethanol, 1 mM sodium pyruvate, and 2 mM L‐glutamine. 64 The TY‐1 cell line, a new HHV‐8+ and EBV− PEL cell line, was previously established by Harutaka Katano. Lymphoma cells were identified from the pericardial effusion of a 45‐year‐old Japanese homosexual patient with AIDS‐PEL and grown in RPMI‐1640 culture medium supplemented with 20% FBS, 10 ng/mL insulin, 10 ng/mL transferrin and 10% filtered pericardial effusion supernatant. Pericardial fluid supplementation was gradually reduced during passage until the cells grew autonomously, and single‐cell cloning was accomplished, resulting in the TY‐1 cell line. 61 HBL‐6 is a cell line established from the ascites of HIV+ PEL patients, both KSHV and EBV positive, whose primary tumor histology has been previously described. 62 Notably, both strains were found negative for cytomegalovirus (CMV), human herpesvirus‐6 (HHV‐6) and HIV. It is crucial to acknowledge that tumor cell lines that have undergone multiple passages may exhibit genetic and physiological drift from their primary tumors and might not respond in the same manner as the primary tumor in its original location. 65

TABLE 2 Summary of frequently used HAL cell lines.

Types of cell line	Cell line name	Origin	HIV	EBV	KSHV/HHV‐8	References	
AIDS‐DLBCL	R	AIDS patients with aggressive posttreatment lymphoma	−	+	−	[55]	
AIDS‐BL	2F7	AIDS‐BL patient	−	+	−	[56]	
2F7‐BR44	AIDS‐BL patient	−	+	−	[57]	
JB	AIDS‐BL patient's microvascular endothelial cell	−	−	−	[58]	
AIDS‐PEL	GTO	AIDS‐PEL patient's pericardial effusion	nm	−	+	[59]	
JSC‐1	AIDS‐PEL patient's ascitic fluid	nm	+	+	[60]	
BCBL‐1	AIDS‐PEL patient	nm	−	+	[55]	
TY‐1	AIDS‐PEL patient's pericardial effusion	nm	−	+	[61]	
HBL‐6	AIDS‐PEL patients	−	+	+	[62]	
Abbreviations: +, positive; −, negative; nm, not mentioned.

2.2.3 AIDS‐DLBCL immunodeficiency mouse model

Daniel P. Widney et al. established a mouse/human xenograft model of AIDS‐DLBCL by mixing 1 × 106 R cell lines (AIDS‐DLBCL subtype) in saline and administering them i.p. into 8‐ to 12‐week‐old female NOD‐SCID mice. The AIDS lymphoma cell line R was originally derived as EBV+, leading to the development of intra‐abdominal tumors in the mice. 66 Regrettably, the research team did not conduct an in‐depth investigation of the tumors originating in the R cell line. As a result, further exploration is necessary to thoroughly assess the success and implications of this modeling.

2.2.4 AIDS‐BL immunodeficiency mouse model

To establish a mouse/human xenograft model of AIDS‐BL, Daniel P. Widney et al. injected 1 × 106 2F7 cells (AIDS‐BL subtype) mixed with saline via i.p. injection into 8‐ to 12‐week‐old female NOD‐SCID mice. 66 Typically, the mice develop palpable abdominal tumors 5–10 weeks after the cell line inoculation, which can later metastasize to the spleen, thymus, and mesenteric lymph nodes. The 2F7 cell line, originating from AIDS‐BL, is EBV‐positive and HIV‐negative. It expresses B cell markers CD19 and CD20 but lacks the CD3 T‐lymphocyte marker on its cell surface. 55 , 56 In a subsequent study, the research team replicated the approach and successfully established the model. 67 The derived and metastatic tumors were histopathologically analogous to human BL. 66 The significance of this model lies in the scarcity of manageable animal models for AIDS‐BL. This mouse model holds potential for investigating interactions between the innate immune system and AIDS‐BL tumor cells, as well as for evaluating potential tumor biomarkers for the disease. Concurrently, Jing Wen et al. first adopted they chose 8‐ to 12‐week‐old C.B‐17 SCID‐Beige female mice. For localized tumor establishment, they injected 2 × 106 2F7‐BR44 or 5 × 106 JB cells in Hank's balanced salt solution (HBSS) subcutaneously (s.c.) into the right side. To induce disseminated disease, 5 × 106 2F7‐BR44 or JB cells were injected intravenously (i.v.) via the tail vein using HBSS. The disseminated models, particularly those employing the 2F7‐BR44 cell line, exhibited higher aggressiveness due to their marked metastatic nature. 57

2.2.5 AIDS‐PEL immunodeficiency mouse model

PEL is an uncommon yet distinctive aggressive form of aggressive non‐Hodgkin B cell lymphoma characterized by the presence of plasmacytoid lymphomatous exudates within the body cavities (such as pleura and peritoneum) and pericardial effusions. This type of lymphoma is frequently associated with infections of KSHV/HHV‐8. 68 Due to the lack of optimal treatment options and the aggressive behavior of PEL, patients diagnosed with this condition typically have a median survival of less than six months. 69 Given these challenges, there is an urgent need to establish an appropriate animal model for PEL to gain a deeper understanding of its underlying pathogenesis.

Cell line‐derived xenograft model

A cell line‐derived xenograft model is constructed by transplanting human‐derived tumor cell lines into immunodeficient mice, and it is one of the most commonly used in vivo models for preclinical pharmacodynamic evaluation of antitumor drugs. Although relatively few mature cell lines of HALs exist, there are still many teams trying the CDX approach (Table 3).

TABLE 3 Details of cell line‐derived xenograft PEL model.

Immunodeficient mice	Age, sex	Cell line	Cell count	Cell resuspension solution	Injection methods	Outcomes	References	
NMRI nude mice	4 weeks, female	BC‐1	2 × 107	50% Matrigel	i.p.	Tumor formation	[29]	
NOD/SCID mice	5–6 weeks, female	BC‐1	3 × 106	nm	i.p.	Ascites within 3–4 weeks	[70]	
4 weeks	BCBL‐1	1 × 107	nm	i.p.	Ascites, weight gain	[60]	
4 weeks	JSC1	1 × 107	nm	i.p.	Ascites, weight gain	[60]	
nm	BCBL‐1	1 × 107/2 × 106	nm	s.c./i.p.	Rapid tumor, massive ascites	[39]	
5 weeks	BCBL‐1	1 × 107	nm	i.p.	Ascites, weight gain	[71]	
4–6 weeks	BCP‐1/HBL‐6	1 × 107	nm	i.v.	Ascites, solid tumors	[72]	
4–6 weeks	BCP‐1/HBL‐6	5–6 × 106	nm	i.p.	Ascites, solid tumors	[72]	
4–6 weeks	BCP‐1/HBL‐6	5–6 × 106	nm	s.c.	Ascites, solid tumors	[72]	
NRJ mice	8–10 weeks, female	BCBL‐1	7 × 106	200 μL PBS	i.p.	Ascites, weight gain	[73]	
8–12 weeks	BCBL‐1	7 × 106	200 μL PBS	i.p.	Ascites; invasion into the liver, lung and spleen without macroscopic lymphoma formation	[36]	
12 weeks	GTO	1 × 107	200 μL PBS	i.p.	Lymphatic ascites within 3 weeks	[59]	
12 weeks	GTO	5 × 106	50 μL PBS	s.c.	Solid lymphomas, at 2 weeks	[59]	
NOJ mice	8–10 weeks	BCBL‐1	7 × 106	200 μL PBS	i.p.	Massive ascites within 3 weeks, weight gain	[74, 75]	
8–10 weeks, male	BCBL‐1	1 × 107	100 μL PBS	i.p.	Massive ascites within 4 weeks, infiltration into the lung, liver, and spleen without macroscopic lymphoma formation	[76]	
NOG mice	nm	BCBL‐1, TY‐1	1 × 107/2 × 106	RPMI‐1640	s.c./ i.p.	Visible tumor within 3 weeks, ascites	[39]	
C.B‐17 SCID mice	8–10 weeks	TY‐1	1 × 107	nm	i.p.	Solid lymphomas	[61, 77]	
8–10 weeks	BCBL‐1	1 × 107	nm	i.p.	Ascites, at 2—4 weeks	[78]	
nm	BCBL‐1	5 × 106	200 μL Matrigel	s.c. /i.p.	Tumor	[79]	
RJ mice	8–10 weeks	BCBL‐1	5 × 106	200 μL PBS	s.c.	Subcutaneous tumor, death at 3–6 weeks	[80]	
Nude RJ mice	6 weeks, female	GTO	1 × 107	200 μL PBS	i.p.	Ascites	[81]	
BRJ mice	8–12 weeks	BCBL‐1	1 × 107	nm	s.c.	Palpable tumor	[82, 83]	
Abbreviations: i.p., intraperitoneally; i.v., intravenously; nm, not mentioned; s.c., subcutaneously.

NMRI nude mice

Eline Boons et al. chose 4‐week‐old female NMRI nude mice as their experimental subjects. These mice were injected s.c. with 2 × 107 BC‐1 cells mixed in 50% Matrigel. This approach successfully established a mouse xenograft model of PEL. 29

NOD/SCID mice

Louna Karam et al. selected 5‐ to 6‐week‐old female NOD/SCID mice for their study. Intraperitoneal injections of 3 × 106 BC‐1 cells were given to these mice, leading to the formation of ascites within a span of 3–4 weeks. 70 Ke Lan et al. constructed a PEL‐transplanted NOD/SCID mouse model by intraperitoneal inoculation of BCBL‐1 or JSC‐1 cells into NOD/SCID mice, injecting 1 × 107 cells per mouse. 60 Lu Dai's team and Shou‐Jiang Gao's team adopted the same approach in several subsequent studies by i.p. injecting 1 × 107 BCBL‐1 cells. 71 , 84 , 85 , 86 , 87 Zahidunnabi Dewan et al. took a different approach by inoculating NOD/SCID mice with BCBL‐1 cells either in the posterior ear region (s.c.) or in the abdomen (i.p.). They found that while BCBL‐1 cells could generate small tumors and lower volumes of ascites at the inoculation site, these cells were unable to infiltrate fully. 39 Chris Boshoff et al. employed three routes of administration for HBL‐6 cells: i.v. (1 × 107 cells/tail vein injection), i.p. (5–6 × 106 cells/injection), and s.c. (5–6 × 106/injection) into 4‐ to 6‐week‐old NOD/SCID mice. All i.p.‐injected mice developed lymphoma exudates similar to PEL, as well as tumor spread to various organ sites. All mice injected s.c. with HBL‐6 cells developed solid lymphomas, indicating that the HBL‐6 cell line can form tumors in NOD/SCID mice and that i.p. injection produces exudative tumors similar to those observed in human PEL, including ascites and spread of lymphoma cells in various organ systems, but few macroscopic form lymphomas. 72

NRJ mice

Kumiko Gotoh et al. opted for inoculating (i.p.) 8‐ to 10‐week‐old female NRJ mice with 7 × 106 BCBL‐1 cells suspended in 200 μL PBS and assessed the tumor load by monitoring body weights and ascites. 73 Similarly, Hiroki Goto et al. used 8‐ to 12‐week‐old NRJ mice, inoculating them i.p. with 7 × 106 BCBL‐1 cells suspended in 200 μL PBS. These mice exhibited significant ascite formation within 3–4 weeks post‐inoculation, indicating rapid and effective implantation of PEL cells. 36 , 88 It is noteworthy that mice inoculated i.p. with BCBL‐1 cells exhibited infiltration in the lungs and liver, although no macroscopic lymphoma formation occurred. This aligns with the characterization of PEL, which is typically identified by a lymphomatous exudate in body cavities rather than a well‐defined tumor mass. 37 , 38 Concurrently, Hiroki Goto et al. established a cell line named GTO from pericardial effusions of a PEL patient. 59 They inoculated 12‐week‐old NRJ mice with the GTO cells through i.p. inoculation of 1 × 107 cells suspended in 200 μL PBS, or s.c. injection in the flank with 5 × 106 cells suspended in 50 μL PBS. Mice that received i.p. inoculations developed significant lymphomatous ascites within 3 weeks, while those inoculated s.c. developed solid lymphomas within 2 weeks. Importantly, no pleural or pericardial effusion was observed in any of the GTO xenograft mice before their demise. 59

NOJ mice

Seiji Okada's research team successfully established an animal model of PEL by intraperitoneal inoculation of 8‐ to 10‐week‐old NOJ mice with 7 × 106 BCBL‐1 cells suspended in 200 μL PBS. Tumor progression was evaluated by measuring changes in body weights and ascites formation. This model led to the development of ascites and widespread infiltration of organs, mirroring the diffuse characteristics of human PEL. 74 , 75 Additionally, the team opted to inject 1 × 107 BCBL‐1 cells suspended in 100 μL PBS into 8‐ to 10‐week‐old NOJ male mice, effectively establishing another PEL model. 76

NOG mice

Zahidunnabi Dewan et al. conducted a study involving the resuspension of BCBL‐1 and TY‐1 cells using serum‐free RPMI‐1640. Subsequently, NOG mice were anesthetized with ether, and the cells were inoculated s.c. in the postauricular region or i.p. at a dose of 1 × 107 or 2 × 106 cells for the respective site. Three weeks after inoculation, all mice were euthanized, and measured for tumor size and ascites volume. The results of the study revealed that NOG mice inoculated with BCBL‐1 and TY‐1 cell lines demonstrated remarkable proficiency in generating substantial tumor masses and ascite volumes. The mice displayed signs of clinical distress near the time of euthanization, including piloerection, weight loss, and cachexia. Furthermore, the consistent growth patterns observed and the retention of the distinctive characteristics of the PEL cells underscored the potential of the NOG mouse model described in this study to provide a promising opportunity for comprehending and investigating the pathogenesis and malignant cellular proliferation associated with PEL. 39

C.B‐17 SCID mice

Harutaka Katano's research team previously succeeded in establishing a KSHV‐positive PEL cell line known as TY‐1. 61 They injected 1 × 107 TY‐1 cells into the peritoneal cavity of 8‐ to 10‐week‐old C.B‐17 SCID mice, leading to the formation of solid lymphomas within the peritoneal cavity, along with instances of exudative lymphoma formation. 61 , 77 By separately collecting exudative and solid lymphoma components, they performed subsequent inoculations. Exudative lymphoma cells were injected into the peritoneal cavity of certain C.B‐17 SCID mice, while solid lymphoma cells were administered s.c. to other mice. After 3–4 weeks, mice injected with exudative lymphomas developed ascites, reflective of exudative lymphomas, whereas mice inoculated with solid lymphomas exhibited subcutaneous tumor growth comprising TY‐1 cells. This lymphoma transplantation process was repeated six times, culminating in the 7th generation. Notably, during these passages, intraperitoneal inoculation of exudative lymphoma cells led to the emergence of both exudative and solid lymphomas within the abdominal cavity. However, mice inoculated with solid lymphomas did not manifest exudative lymphomas in any of their cavities. 61

Gaston Picchio et al. employed intraperitoneal inoculation of 8‐ to 10‐week‐old C.B‐17 SCID/SCID mice with 1 × 107 BCBL‐1 cells (KSHV+EBV−), which resulted in the establishment of tumor growth and ascites formation within 2–4 weeks post‐inoculation. 78 Michelle Staudt et al. inoculated C.B‐17 SCID mice either by s.c. injection of 5 × 106 BCBL‐1 cells, mixed with 200 μL factor‐depleted Matrigel, into the right side of mice; or by intraperitoneal injection. Among these trials, tumors developed in six of seven mice treated with BCBL‐1 cells and factor‐depleted Matrigel. In contrast, mice receiving BCBL‐1 cells without Matrigel did not exhibit tumor formation even after a period of 28 days. These results indicated that Matrigel supplementation enhanced tumor formation in BCBL‐1 cells within the subcutaneous microenvironment of SCID mice. The amalgamation of PEL cells and Matrigel presents an expedited in vivo model of KSHV for studying tumorigenesis in PEL. 79

RJ/BRJ/nude RJ mice

Yoshioki Shir Aishi et al. inoculated BC‐3 cells into the peritoneal cavity of RJ mice, resulting in the substantial accumulation of ascites fluid. Conversely, subcutaneous injection of BCBL‐1 resulted in the development of solid lymphomas. In the subcutaneous xenograft mouse model, RJ mice aged 8–10 weeks were subjected to s.c. inoculation with 5 × 106 BCBL‐1 cells suspended in 200 μL of PBS. Consequently, the mice exhibited pronounced growth of sizable subcutaneous tumors, displayed clinical indications nearing death, including piloerection, weight loss, and cachexia, and succumbed within 3–6 weeks post‐transplantation. 80 Seiji Okada's research team employed the s.c. injection of 1 × 107 BCBL‐1 cells into 8‐ to 12‐week‐old male Balb/c RJ mice (BRJ mice), leading to the successful development of solid PEL‐derived tumors in this mouse model. 82 , 89 Masud Alam et al. employed a xenograft technique involving GTO cells and 6‐week‐old Nude‐Rag2/Jak3 double‐deficient (Nude‐RJ) female mice. In this approach, 1 × 107 GTO cells were resuspended in 200 μL of PBS and i.p. injection into the abdominal region of Nude‐RJ mice to establish the PEL model. 81

Patient‐derived xenograft model

The PDX model offers notable advantages, including the representation of realistic tumor cell heterogeneity, ease of tumor extraction, and straightforward monitoring of tumor size. 90 However, it is important to note that the microenvironment in this model differs significantly from that of tumors grown in natural organs. 91 Hiroki Goto et al. pursued a direct xenograft mouse model by i.p. injecting primary PEL cells into NRJ mice. The basis for this approach stemmed from a case involving a 39‐year‐old HIV+ Japanese man who was hospitalized due to acute pericardial tamponade. Subsequently, PEL cells were isolated from his pericardial effusion, confirming the presence of PEL. PEL cells were isolated from his pericardial effusion and immediately injected i.p. into 8‐ to 12‐week‐old NRJ mice. This procedure prompted the rapid development of ascites within 14 days, and a segment of the ascites was collected immediately postmortem. The isolated cells were referred to as ‘PEL‐NRJ’ cells. For the xenograft mouse model, 1 × 107 PEL‐NRJ cells, without undergoing ex vivo culture, were suspended in 200 μL of PBS and injected into the peritoneal cavity of NRJ mice. Assessment of tumor load was conducted by measuring the ascites volume on day 14. Importantly, PEL‐NRJ cells demonstrated in vivo implantation, leading to the early formation of ascites in comparison to previously reported cell lines like BCBL‐1 92 (Figure 2).

FIGURE 2 The flowchart of the patient‐derived xenograft model in Hiroki Goto's study.

Michael S. McGrath's research team embarked on an exploration of modeling efficiency using three different approaches. They started by procuring effusions from peritoneal or pleural cavities of two distinct HIV+ PEL patients via paracentesis. Supernatants were collected from these effusions, and cells were subsequently isolated. Some cells underwent overnight culture, while others were preserved through freezing for future use. 93 , 94 At the time of use, the frozen cells were rapidly thawed, resuspended, and directly injected without undergoing culture. As part of their methodology, 8‐week‐old immunodeficient mice received an intraperitoneal injection of 0.1 mL of antisialic acid‐GM1 antiserum at least 24 hours before intraperitoneal inoculation of PEL cells. This antibody preconditioning approach has been demonstrated to enhance tumor implantation in other systems. 95 In the first experiment, the team i.p. injected 1 × 107 cultured cells into seven C.B‐17‐SCID mice. Among these, three received cell‐enriched culture supernatant, while the remaining four mice were administered macrophage‐rich adherent material scraped from cell culture flasks. Subsequently, the second experiment involved four ICR‐SCID mice receiving various cell doses from different culture conditions, including injections of a mixture of cells and supernatant, as well as 1 × 107 frozen cells. 93 The third experiment revolved around thawed PEL cells that were stained with anti‐CD3 or anti‐CD14 antibodies and then sorted using flow cytometric fluorescence sorting (FACS). The sorted cells were subsequently injected into mice, with different groups receiving distinct cell subpopulations. The outcomes of these experiments were as follows. In Experiment One, at 14 weeks post PEL injection, five out of seven animals developed systemic high‐grade lymphoma or lymphoproliferative disease. In Experiment Two, ten out of fifteen mice developed aggressive murine large T‐cell lymphoma and lymphoproliferative disease affecting the spleen, liver, and bone marrow. In Experiment Three, the incidence of T‐cell lymphoma in mice receiving material injected with human PEL‐associated CD14 cells exceeded 50%. The injection of PEL‐containing human macrophages played a pivotal role in the development of fatal lymphomas in these mice. 96 , 97 , 98 , 99 Notably, injections of human large‐cell lymphoma ascites into animals resulted in the development of mouse high‐grade large‐cell lymphoma. 100

3 PRIMATE MODELS FOR HAL

3.1 Cynomolgus monkeys (Macaca fascicularis)

Monkeys infected with simian immunodeficiency virus (SIV) have been observed to develop B cell NHL that is pathologically and clinically similar to HIV‐infected patients, including lymphoblastic, pleomorphic, immunoblastic, centroblastic, and ‘Burkitt‐like’ subtypes. 96 , 101 , 102 , 103 , 104 , 105 However, using monkey models presents challenges due to their high cost and the complexities of caring for them, and only a small percentage of SIV‐infected animals develop BL‐like tumors. 105 As early as 1983, researchers noted an increased occurrence of lymphoma in SIV‐infected macaque monkeys (macaques). 97 , 98 Notably, Per Putkonen et al. demonstrated an elevated lymphoma incidence in SIV‐infected cynomolgus monkeys over a 2‐year monitoring period. These monkeys exhibited lymphadenopathy, splenomegaly, diarrhea, weight loss, neurological symptoms, and a remarkably high occurrence of malignant lymphomas (39%). All identified lymphomas were characterized as high‐grade malignancies originating from B cells. 99

A pivotal study on NHL was conducted by Hans Feichtinger et al. using a cynomolgus monkey model. After administering SIV derived from Black Mangabey to the monkeys, a substantial proportion (38%) of them developed a highly malignant B cell lymphoma that shared immunophenotypic, histological and clinical features with HALs. 106 Subsequent research by the same team revealed the presence of an EBV‐like B‐lymphotropic herpesvirus within the cynomolgus monkey. This virus expressed nuclear molecules akin to EBV‐associated antigens. These findings underscored the value of the cynomolgus monkey model, particularly in understanding cynomolgus monkey B lymphophile herpesvirus‐associated B‐cell lymphoma in the context of Mangabeus Nigricans infection. This model closely mirrors EBV‐associated lymphoma in HIV patients, thereby offering a model to study the interplay of immunosuppressive and oncogenic factors in HALs. 101 Subsequently, Esmeralda Castaños‐Vélez et al. leveraged the cynomolgus monkey model alongside the SCID mouse model. 107 Their work reaffirmed that simian HAL (sHAL) shares similar immunological characteristics with human B cell‐derived diffuse large cell lymphoma, a critical insight for understanding HAL. 102 , 107

3.2 Rhesus macaques (rhesus monkeys, Macaca mulatta)

Similar to cynomolgus monkeys, SIV‐infected rhesus macaques have also been documented to develop lymphomas. 108 , 109 , 110 , 111 In contrast, Sabine Pingel et al. reported a much lower incidence of lymphoma in rhesus monkeys (16%), and this discrepancy may be the result of different strains of infected SIV or different susceptibility of the species to SIV. 111 Despite this, both monkey models exhibited high‐grade non‐Hodgkin lymphomas (NHL) with extranodal growth patterns and comparable histological subtypes. 111 Christian Buske et al. conducted a study involving SIV‐infected rhesus macaques, during which they identified transforming growth factor‐β (TGF‐β) as a cytokine that inhibits the growth of sHALs. They demonstrated that TGF‐β could potentially serve as a therapeutic agent for sHAL treatment by impeding lymphoma cell proliferation and countering the effects of growth‐promoting cytokines. 96 Although HAL in cynomolgus monkeys and rhesus monkeys shares various histological, immunological and clinical similarities with human HAL, disparities in lymphoma biology exist between macaques and humans. Some of these disparities include the absence of primary exudative lymphomas in macaques, the challenges in diagnosing PCNSL in monkeys, and a higher incidence of infection with EBV‐monkey homologues in macaques compared to EBVs found in human patients. These distinctions have limited the applicability of these monkey models. 96 , 105 Future refinements for enhancing these animal models include employing less virulent strains of SIV to extend the lifespan of monkeys, utilizing tumor promoters to increase the incidence of sHAL, and identifying predictive markers of lymphoma to facilitate the early identification of monkeys prone to developing lymphoma. 112

4 LIMITATIONS OF THE REVIEW

This review has certain limitations that should be acknowledged. Firstly, the available literature on animal models of HAL is limited, with a considerable portion of it being relatively outdated. This scarcity of studies could be attributed to the stringent requirements associated with HIV research and the comparatively low incidence of HALs. Thus, it is crucial to generate greater public awareness about this disease to foster more comprehensive research efforts. Additionally, previous studies have described a large number of PEL models and fewer DLBCL and BL models, but clinically PEL patients are exceptionally scarce, whereas DLBCL and BL are the most common subtypes worldwide. So the PEL model may be inpracticable in the laboratory. Lastly, a noteworthy challenge arises from the lack of well‐defined criteria for assessing the stability and reliability of different models across studies. The absence of more in‐depth mechanistic studies further compounds this issue, as it hinders the demonstration of the distinctiveness and reliability of individual models utilized in these studies.

5 CONCLUSIONS AND PERSPECTIVES

Up until now, animal models of HAL remain in a relatively nascent stage. The models described here have greatly increased our understanding of human HAL. Nevertheless, there is considerable room for improvement in the development of these animal models, such as standardization of modeling success criteria and monitoring the presence of HIV viral loads or viral reservoirs in these animals. The development of new animal models and the improvement of existing ones may contribute to a better understanding of the pathogenesis and treatment of HALs, enable the testing of therapeutic agents against these diseases, and ultimately lead to more satisfactory outcomes in patients with these malignancies. While PEL as the most explored animal model, which may be because tumor cells in the abdominal and pleural effusions of patients with PEL are easier to obtain and purify, the incidence rate of PEL is extremely low and it is clinically rare.  Therefore, the pratical value of the PEL mouse model might not be as significant as initially believed. In future, a promising approach could involve establishing HAL mouse models by utilizing patient‐derived xenografts from DLBCL or BL cases. This shift may facilitate a more effective exploration of disease‐specific events and mechanisms.

AUTHOR CONTRIBUTIONS

Yao Liu and Fujie Zhang had the idea for this review. Qing Xiao and Liuyue Zhai drafted the manuscript and prepared the figures and tables. Xiaomei Zhang, Yi Liu, Jun Li and Xiaoqing Xie revised the manuscript. Guofa Xu, Sanxiu He, Huihui Fu, Yifeng Tang edited and visualized the figures and tables. All authors contributed to the article and approved the submitted version.

FUNDING INFORMATION

This study was supported by the Natural Science Foundation of Chongqing, China (CSTB2022NSCQ‐MSX1150), the Fundamental Research Funds for the Central Universities (2022CDJYGRH‐001) and the Chongqing Professional Talents Plan (cstc2022ycjh‐bgzxm0048).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

None.

ACKNOWLEDGMENTS

Thanks to all authors for their contribution to this manuscript.
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REFERENCES

1 Xiao Q , Yan L , Han J , et al. Metabolism‐dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4(+) T lymphocytes in HIV‐infected immune non‐responders. EBioMedicine. 2022;86 :104382.36462403
2 Wang F , Xiang P , Zhao H , et al. A retrospective study of distribution of HIV associated malignancies among inpatients from 2007 to 2020 in China. Sci Rep. 2021;11 (1 ):24353.34934097
3 Dal Maso L , Franceschi S . Epidemiology of non‐Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet Oncol. 2003;4 (2 ):110‐119.12573353
4 Wang C , Liu J , Liu Y . Progress in the treatment of HIV‐associated lymphoma when combined with the antiretroviral therapies. Front Oncol. 2021;11 :798008.35096597
5 Noy A . Optimizing treatment of HIV‐associated lymphoma. Blood. 2019;134 (17 ):1385‐1394.30992269
6 Hegde U , Filie A , Little RF , et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B‐cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood. 2005;105 (2 ):496‐502.15358629
7 Hleyhel M , Belot A , Bouvier AM , et al. Risk of AIDS‐defining cancers among HIV‐1‐infected patients in France between 1992 and 2009: results from the FHDH‐ANRS CO4 cohort. Clin Infect Dis. 2013;57 (11 ):1638‐1647.23899679
8 Coghill AE , Shiels MS , Suneja G , Engels EA . Elevated cancer‐specific mortality among HIV‐infected patients in the United States. J Clin Oncol. 2015;33 (21 ):2376‐2383.26077242
9 Kimani SM , Painschab MS , Horner MJ , et al. Epidemiology of haematological malignancies in people living with HIV. Lancet HIV. 2020;7 (9 ):e641‐e651.32791045
10 Poizot‐Martin I , Lions C , Allavena C , et al. Spectrum and incidence trends of AIDS‐ and non‐AIDS‐defining cancers between 2010 and 2015 in the French Dat'AIDS cohort. Cancer Epidemiol Biomarkers Prev. 2021;30 (3 ):554‐563.33310788
11 Carbone A , Gloghini A , Serraino D , Spina M , Tirelli U , Vaccher E . Immunodeficiency‐associated Hodgkin lymphoma. Expert Rev Hematol. 2021;14 (6 ):547‐559.34044724
12 Carbone A , Vaccher E , Gloghini A . Hematologic cancers in individuals infected by HIV. Blood. 2022;139 (7 ):995‐1012.34469512
13 Pongas GN , Ramos JC . HIV‐associated lymphomas: progress and new challenges. J Clin Med. 2022;11 (5 ):1447.35268547
14 Hensel ME , Arenas‐Gamboa AM . A neglected animal model for a neglected disease: Guinea pigs and the search for an improved animal model for human brucellosis. Front Microbiol. 2018;9 :2593.30429834
15 Steeg PS . Targeting metastasis. Nat Rev Cancer. 2016;16 (4 ):201‐218.27009393
16 Leonard JM , Abramczuk JW , Pezen DS , et al. Development of disease and virus recovery in transgenic mice containing HIV proviral DNA. Science. 1988;242 (4886 ):1665‐1670.3201255
17 Feinberg MB , Moore JP . AIDS vaccine models: challenging challenge viruses. Nat Med. 2002;8 (3 ):207‐210.11875482
18 Tinkle BT , Ueda H , Ngo L , et al. Transgenic dissection of HIV genes involved in lymphoid depletion. J Clin Invest. 1997;100 (1 ):32‐39.9202054
19 Hanna Z , Kay DG , Cool M , Jothy S , Rebai N , Jolicoeur P . Transgenic mice expressing human immunodeficiency virus type 1 in immune cells develop a severe AIDS‐like disease. J Virol. 1998;72 (1 ):121‐132.9420207
20 van Maanen M , Sutton RE . Rodent models for HIV‐1 infection and disease. Curr HIV Res. 2003;1 (1 ):121‐130.15043216
21 Carroll VA , Lafferty MK , Marchionni L , Bryant JL , Gallo RC , Garzino‐Demo A . Expression of HIV‐1 matrix protein p17 and association with B‐cell lymphoma in HIV‐1 transgenic mice. Proc Natl Acad Sci USA. 2016;113 (46 ):13168‐13173.27799525
22 Taniguchi H , He M , Wu P , et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron. 2011;71 (6 ):995‐1013.21943598
23 Ceredig RA , Massotte D . Fluorescent knock‐in mice to decipher the physiopathological role of G protein‐coupled receptors. Front Pharmacol. 2014;5 :289.25610398
24 Bertram K , Leary PJ , Boudesco C , et al. Inhibitors of Bcl‐2 and Bruton's tyrosine kinase synergize to abrogate diffuse large B‐cell lymphoma growth in vitro and in orthotopic xenotransplantation models. Leukemia. 2022;36 (4 ):1035‐1047.34795418
25 Kim Y , Turner D , Nelson J , Dobrinski I , McEntee M , Travis AJ . Production of donor‐derived sperm after spermatogonial stem cell transplantation in the dog. Reproduction. 2008;136 (6 ):823‐831.18768666
26 Wu CH , Yang CY , Wang L , et al. Cutaneous T‐cell lymphoma PDX drug screening platform identifies cooperation between inhibitions of PI3Kα/δ and HDAC. J Invest Dermatol. 2021;141 (2 ):364‐373.32603749
27 Wen T , Sun G , Jiang W , et al. Histone deacetylases inhibitor chidamide synergizes with humanized PD1 antibody to enhance T‐cell chemokine expression and augment Ifn‐γ response in NK‐T cell lymphoma. EBioMedicine. 2023;87 :104420.36592514
28 Klöß S , Dehmel S , Braun A , Parnham MJ , Köhl U , Schiffmann S . From cancer to immune‐mediated diseases and tolerance induction: lessons learned from immune oncology and classical anti‐cancer treatment. Front Immunol. 2020;11 :1423.32733473
29 Boons E , Vanstreels E , Jacquemyn M , et al. Human exportin‐1 is a target for combined therapy of HIV and AIDS related lymphoma. EBioMedicine. 2015;2 (9 ):1102‐1113.26501108
30 Makino S , Kunimoto K , Muraoka Y , Mizushima Y , Katagiri K , Tochino Y . Breeding of a non‐obese, diabetic strain of mice. Jikken Dobutsu. 1980;29 (1 ):1‐13.6995140
31 Anderson MS , Bluestone JA . The NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23 :447‐485.15771578
32 Bosma GC , Custer RP , Bosma MJ . A severe combined immunodeficiency mutation in the mouse. Nature. 1983;301 (5900 ):527‐530.6823332
33 Shultz LD , Schweitzer PA , Christianson SW , et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz‐scid mice. J Immunol. 1995;154 (1 ):180‐191.7995938
34 Dick JE . Normal and leukemic human stem cells assayed in SCID mice. Semin Immunol. 1996;8 (4 ):197‐206.8883142
35 McBride BW , Easterbrook LM , Farrar GH . Human immunodeficiency virus infection of xenografted SCID‐beige mice. J Med Virol. 1995;47 (2 ):130‐138.8830116
36 Goto H , Kariya R , Shimamoto M , et al. Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF‐κB pathway. Cancer Sci. 2012;103 (4 ):775‐781.22320346
37 Nador RG , Cesarman E , Chadburn A , et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma‐associated herpes virus. Blood. 1996;88 (2 ):645‐656.8695812
38 Chen YB , Rahemtullah A , Hochberg E . Primary effusion lymphoma. Oncologist. 2007;12 (5 ):569‐576.17522245
39 Dewan MZ , Terunuma H , Toi M , et al. Potential role of natural killer cells in controlling growth and infiltration of AIDS‐associated primary effusion lymphoma cells. Cancer Sci. 2006;97 (12 ):1381‐1387.16995875
40 Shinkai Y , Rathbun G , Lam KP , et al. RAG‐2‐deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68 (5 ):855‐867.1547487
41 Nosaka T , van Deursen JMA , Tripp RA , et al. Defective lymphoid development in mice lacking Jak3. Science. 1995;270 (5237 ):800‐802.7481769
42 Ono A , Hattori S , Kariya R , et al. Comparative study of human hematopoietic cell engraftment into BALB/c and C57BL/6 strain of rag‐2/jak3 double‐deficient mice. J Biomed Biotechnol. 2011;2011 :539748.21331358
43 Kariya R , Matsuda K , Gotoh K , Vaeteewoottacharn K , Hattori S , Okada S . Establishment of nude mice with complete loss of lymphocytes and NK cells and application for in vivo bio‐imaging. In Vivo. 2014;28 (5 ):779‐784.25189889
44 Schuler W , Bosma MJ . Nature of the scid defect: a defective VDJ recombinase system. Curr Top Microbiol Immunol. 1989;152 :55‐62.2805798
45 Kamel‐Reid S , Letarte M , Sirard C , et al. A model of human acute lymphoblastic leukemia in immune‐deficient SCID mice. Science. 1989;246 (4937 ):1597‐1600.2595371
46 Mosier DE , Gulizia RJ , Baird SM , Wilson DB . Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335 (6187 ):256‐259.2970594
47 Ito M , Hiramatsu H , Kobayashi K , et al. NOD/SCID/gamma (c) (null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100 (9 ):3175‐3182.12384415
48 Greiner DL , Hesselton RA , Shultz LD . SCID mouse models of human stem cell engraftment. Stem Cells. 1998;16 (3 ):166‐177.9617892
49 Shultz LD , Lyons BL , Burzenski LM , et al. Human lymphoid and myeloid cell development in NOD/LtSz‐scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174 (10 ):6477‐6489.15879151
50 Okada S , Harada H , Ito T , Saito T , Suzu S . Early development of human hematopoietic and acquired immune systems in new born NOD/Scid/Jak3null mice intrahepatic engrafted with cord blood‐derived CD34+ cells. Int J Hematol. 2008;88 (5 ):476‐482.19039627
51 Park SY , Saijo K , Takahashi T , et al. Developmental defects of lymphoid cells in Jak3 kinase‐deficient mice. Immunity. 1995;3 (6 ):771‐782.8777722
52 Söderstrøm I , Bergman ML , Colucci F , Lejon K , Bergqvist I , Holmberg D . Establishment and characterization of RAG‐2 deficient non‐obese diabetic mice. Scand J Immunol. 1996;43 (5 ):525‐530.8633210
53 Sakano D , Inoue A , Enomoto T , et al. Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance. Sci Rep. 2020;10 (1 ):12187.32699230
54 Knudsen ES , Balaji U , Mannakee B , et al. Pancreatic cancer cell lines as patient‐derived avatars: genetic characterisation and functional utility. Gut. 2018;67 (3 ):508‐520.28073890
55 Widney D , Boscardin WJ , Kasravi A , Mart&iacute;nez‐Maza O . Expression and function of CD28 on Epstein‐Barr virus‐positive B cell lines and AIDS‐associated non‐Hodgkin's lymphoma cell lines. Tumour Biol. 2003;24 (2 ):82‐93.12853703
56 Ng VL , Hurt MH , Fein CL , et al. IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificity and VH‐gene putative somatic mutation analysis. Blood. 1994;83 (4 ):1067‐1078.8111047
57 Wen J , Wu D , Qin M , et al. Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice. Nat Biomed Eng. 2019;3 (9 ):706‐716.31384008
58 Moses AV , Williams SE , Strussenberg JG , et al. HIV‐1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS‐associated B‐cell lymphomas. Nat Med. 1997;3 (11 ):1242‐1249.9359699
59 Goto H , Kojima Y , Nagai H , Okada S . Establishment of a CD4‐positive cell line from an AIDS‐related primary effusion lymphoma. Int J Hematol. 2013;97 (5 ):624‐633.23605439
60 Lan K , Murakami M , Bajaj B , et al. Inhibition of KSHV‐infected primary effusion lymphomas in NOD/SCID mice by gamma‐secretase inhibitor. Cancer Biol Ther. 2009;8 (22 ):2136‐2143.19783901
61 Katano H , Hoshino Y , Morishita Y , et al. Establishing and characterizing a CD30‐positive cell line harboring HHV‐8 from a primary effusion lymphoma. J Med Virol. 1999;58 (4 ):394‐401.10421407
62 Knowles DM , Inghirami G , Ubriaco A , Dalla‐Favera R . Molecular genetic analysis of three AIDS‐associated neoplasms of uncertain lineage demonstrates their B‐cell derivation and the possible pathogenetic role of the Epstein‐Barr virus. Blood. 1989;73 (3 ):792‐799.2537119
63 Cannon JS , Ciufo D , Hawkins AL , et al. A new primary effusion lymphoma‐derived cell line yields a highly infectious Kaposi's sarcoma herpesvirus‐containing supernatant. J Virol. 2000;74 (21 ):10187‐10193.11024147
64 Renne R , Zhong W , Herndier B , et al. Lytic growth of Kaposi's sarcoma‐associated herpesvirus (human herpesvirus 8) in culture. Nat Med. 1996;2 (3 ):342‐346.8612236
65 Stone HB , Bernhard EJ , Coleman CN , et al. Preclinical data on efficacy of 10 drug‐radiation combinations: evaluations, concerns, and recommendations. Transl Oncol. 2016;9 (1 ):46‐56.26947881
66 Widney DP , Olafsen T , Wu AM , et al. Levels of murine, but not human, CXCL13 are greatly elevated in NOD‐SCID mice bearing the AIDS‐associated Burkitt lymphoma cell line, 2F7. PloS One. 2013;8 (8 ):e72414.23936541
67 Daniels‐Wells TR , Widney DP , Leoh LS , Martínez‐Maza O , Penichet ML . Efficacy of an anti‐transferrin receptor 1 antibody against AIDS‐related non‐Hodgkin lymphoma: a brief communication. J Immunother. 2015;38 (8 ):307‐310.26325374
68 Patel S , Xiao P . Primary effusion lymphoma. Arch Pathol Lab Med. 2013;137 (8 ):1152‐1154.23899073
69 Boulanger E , Gérard L , Gabarre J , et al. Prognostic factors and outcome of human herpesvirus 8‐associated primary effusion lymphoma in patients with AIDS. J Clin Oncol. 2005;23 (19 ):4372‐4380.15994147
70 Karam L , Abou Staiteieh S , Chaaban R , et al. Anticancer activities of parthenolide in primary effusion lymphoma preclinical models. Mol Carcinog. 2021;60 (8 ):567‐581.34101920
71 Gruffaz M , Zhou S , Vasan K , et al. Repurposing cytarabine for treating primary effusion lymphoma by targeting Kaposi's sarcoma‐associated herpesvirus latent and lytic replications. MBio. 2018;9 (3 ):e00756‐18.29739902
72 Boshoff C , Gao SJ , Healy LE , et al. Establishing a KSHV+ cell line (BCP‐1) from peripheral blood and characterizing its growth in nod/SCID mice. Blood. 1998;91 (5 ):1671‐1679.9473233
73 Gotoh K , Kariya R , Alam MM , et al. The antitumor effects of methyl‐β‐cyclodextrin against primary effusion lymphoma via the depletion of cholesterol from lipid rafts. Biochem Biophys Res Commun. 2014;455 (3–4 ):285‐289.25446086
74 Takahashi‐Makise N , Suzu S , Hiyoshi M , et al. Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF‐kappaB pathway. Int J Cancer. 2009;125 (6 ):1464‐1472.19521981
75 Towata T , Komizu Y , Suzu S , Matsumoto Y , Ueoka R , Okada S . Hybrid liposomes inhibit the growth of primary effusion lymphoma in vitro and in vivo. Leuk Res. 2010;34 (7 ):906‐911.20074798
76 Kariya R , Taura M , Suzu S , Kai H , Katano H , Okada S . HIV protease inhibitor Lopinavir induces apoptosis of primary effusion lymphoma cells via suppression of NF‐κB pathway. Cancer Lett. 2014;342 (1 ):52‐59.24012878
77 Katano H , Suda T , Morishita Y , et al. Human herpesvirus 8‐associated solid lymphomas that occur in AIDS patients take anaplastic large cell morphology. Mod Pathol. 2000;13 (1 ):77‐85.10658913
78 Picchio GR , Sabbe RE , Gulizia RJ , McGrath M , Herndier BG , Mosier DE . The KSHV/HHV8‐infected BCBL‐1 lymphoma line causes tumors in SCID mice but fails to transmit virus to a human peripheral blood mononuclear cell graft. Virology. 1997;238 (1 ):22‐29.9375005
79 Staudt MR , Kanan Y , Jeong JH , Papin JF , Hines‐Boykin R , Dittmer DP . The tumor microenvironment controls primary effusion lymphoma growth in vivo. Cancer Res. 2004;64 (14 ):4790‐4799.15256448
80 Shiraishi Y , Gotoh K , Towata T , et al. Therapeutic effects of γ‐irradiation in a primary effusion lymphoma mouse model. Exp Ther Med. 2010;1 (1 ):79‐84.23136597
81 Masud Alam M , Kariya R , Kawaguchi A , Matsuda K , Kudo E , Okada S . Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress. Apoptosis. 2016;21 (10 ):1191‐1201.27484211
82 Ueno M , Kariya R , Sittithumcharee G , Okada S . Cucurbitacin B induces apoptosis of primary effusion lymphoma via disruption of cytoskeletal organization. Phytomedicine. 2021;85 :153545.33799222
83 Sittithumcharee G , Kariya R , Kasemsuk T , Saeeng R , Okada S . Antitumor effect of acanthoic acid against primary effusion lymphoma via inhibition of c‐FLIP. Phytother Res. 2021;35 (12 ):7018‐7026.34779075
84 Dai L , Lin Z , Qiao J , Chen Y , Flemington EK , Qin Z . Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma. Oncogene. 2017;36 (35 ):5068‐5074.28459467
85 Dai L , Trillo‐Tinoco J , Cao Y , et al. Targeting HGF/c‐MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood. 2015;126 (26 ):2821‐2831.26531163
86 Dai L , Cao Y , Chen Y , Parsons C , Qin Z . Targeting xCT, a cystine‐glutamate transporter induces apoptosis and tumor regression for KSHV/HIV‐associated lymphoma. J Hematol Oncol. 2014;7 :30.24708874
87 Dai L , Trillo‐Tinoco J , Bai L , et al. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL). PloS One. 2014;9 (2 ):e90349.24587336
88 Goto H , Matsuda K , Srikoon P , et al. Potent antitumor activity of zoledronic acid‐induced Vγ9Vδ2 T cells against primary effusion lymphoma. Cancer Lett. 2013;331 (2 ):174‐182.23321500
89 Matsuno T , Kariya R , Yano S , et al. Diethyldithiocarbamate induces apoptosis in HHV‐8‐infected primary effusion lymphoma cells via inhibition of the NF‐κB pathway. Int J Oncol. 2012;40 (4 ):1071‐1078.22200846
90 Stein AP , Swick AD , Smith MA , et al. Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies. Cancer Med. 2015;4 (5 ):699‐712.25619980
91 Lee JW , Stone RL , Lee SJ , et al. EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin Cancer Res. 2010;16 (9 ):2562‐2570.20388851
92 Goto H , Kojima Y , Matsuda K , et al. Efficacy of anti‐CD47 antibody‐mediated phagocytosis with macrophages against primary effusion lymphoma. Eur J Cancer. 2014;50 (10 ):1836‐1846.24726056
93 Crowe S , Mills J , McGrath MS . Quantitative immunocytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages. AIDS Res Hum Retrovir. 1987;3 (2 ):135‐145.3113464
94 Crowe SM , Mills J , Kirihara J , Boothman J , Marshall JA , McGrath MS . Full‐length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4‐expressing T‐lymphoblastoid cells. AIDS Res Hum Retrovir. 1990;6 (8 ):1031‐1037.1977427
95 Bryant J , Pham L , Yoshimura L , Tamayo A , Ordonez N , Ford RJ . Development of intermediate‐grade (mantle cell) and low‐grade (small lymphocytic and marginal zone) human non‐Hodgkin's lymphomas xenotransplanted in severe combined immunodeficiency mouse models. Lab Investig. 2000;80 (4 ):557‐573.10780672
96 Buske C , Hannig H , Schneider EM , et al. Transforming growth factor beta is a growth‐inhibitory cytokine of B cell lymphoma in SIV‐infected macaques. AIDS Res Hum Retrovir. 1999;15 (16 ):1477‐1485.10555111
97 Hunt RD , Blake BJ , Chalifoux LV , Sehgal PK , King NW , Letvin NL . Transmission of naturally occurring lymphoma in macaque monkeys. Proc Natl Acad Sci USA. 1983;80 (16 ):5085‐5089.6576377
98 King NW , Hunt RD , Letvin NL . Histopathologic changes in macaques with an acquired immunodeficiency syndrome (AIDS). Am J Pathol. 1983;113 (3 ):382‐388.6316791
99 Putkonen P , Kaaya EE , Böttiger D , et al. Clinical features and predictive markers of disease progression in cynomolgus monkeys experimentally infected with simian immunodeficiency virus. Aids. 1992;6 (3 ):257‐263.1348944
100 Zenger E , Abbey NW , Weinstein MD , et al. Injection of human primary effusion lymphoma cells or associated macrophages into severe combined immunodeficient mice causes murine lymphomas. Cancer Res. 2002;62 (19 ):5536‐5542.12359765
101 Feichtinger H , Li SL , Kaaya E , et al. A monkey model for Epstein Barr virus‐associated lymphomagenesis in human acquired immunodeficiency syndrome. J Exp Med. 1992;176 (1 ):281‐286.1319458
102 Rezikyan S , Kaaya EE , Ekman M , et al. B‐cell lymphomagenesis in SIV‐immunosuppressed cynomolgus monkeys. Int J Cancer. 1995;61 (4 ):574‐579.7759163
103 Hannig H , Mätz‐Rensing K , Kuhn EM , et al. Cytokine gene transcription in simian immunodeficiency virus and human immunodeficiency virus‐associated non‐Hodgkin lymphomas. AIDS Res Hum Retrovir. 1997;13 (18 ):1589‐1596.9430251
104 Maggiorella MT , Monardo F , Koanga‐Mogtomo ML , et al. Detection of infectious simian immunodeficiency virus in B‐ and T‐cell lymphomas of experimentally infected macaques. Blood. 1998;91 (9 ):3103‐3111.9558363
105 Kahnt K , Mätz‐Rensing K , Hofmann P , Stahl‐Hennig C , Kaup FJ . SIV‐associated lymphomas in rhesus monkeys (Macaca mulatta) in comparison with HIV‐associated lymphomas. Vet Pathol. 2002;39 (1 ):42‐55.12102218
106 Feichtinger H , Putkonen P , Parravicini C , et al. Malignant lymphomas in cynomolgus monkeys infected with simian immunodeficiency virus. Am J Pathol. 1990;137 (6 ):1311‐1315.1701962
107 Castaños‐Vélez E , Heiden T , Lindvall C , et al. Simian AIDS‐related lymphoma growth in severe combined immunodeficiency mice is independent of karyotypic abnormalities or Bcl‐6 mutations. AIDS Res Hum Retrovir. 2002;18 (5 ):383‐390.11897040
108 Baskin GB , Martin LN , Rangan SR , et al. Transmissible lymphoma and simian acquired immunodeficiency syndrome in rhesus monkeys. J Natl Cancer Inst. 1986;77 (1 ):127‐139.3014195
109 Daniel MD , Letvin NL , King NW , et al. Isolation of T‐cell tropic HTLV‐III‐like retrovirus from macaques. Science. 1985;228 (4704 ):1201‐1204.3159089
110 Benveniste RE , Arthur LO , Tsai CC , et al. Isolation of a lentivirus from a macaque with lymphoma: comparison with HTLV‐III/LAV and other lentiviruses. J Virol. 1986;60 (2 ):483‐490.3021982
111 Pingel S , Hannig H , Mätz‐Rensing K , Kaup FJ , Hunsmann G , Bodemer W . Detection of Epstein‐Barr virus small RNAs EBER1 and EBER2 in lymphomas of SIV‐infected rhesus monkeys by in situ hybridization. Int J Cancer. 1997;72 (1 ):160‐165.9212238
112 Baskin GB , Cremer KJ , Levy LS . Comparative pathobiology of HIV‐ and SIV‐associated lymphoma. AIDS Res Hum Retrovir. 2001;17 (8 ):745‐751.11429114
