Human immunodeficiency virus infection of human lymph nodes in the SCID-hu mouse.

Abstract

The SCID-hu mouse is a small animal in which human hematolymphoid organs can be engrafted and maintained in vivo. In this study, parameters are described for reproducible infection of SCID-hu mice after i.v. inoculation. Infection was found to be dependent upon the time after inoculation, the virus isolate, the titer of virus, and the human target organ implanted into the mouse. Ten to 14 days after the i.v. administration of HIV isolates derived freshly from patients (e.g., JR-CSF, JR-FL, SM), 100% of engrafted human lymph nodes in SCID-hu mice were infected; greater than 95% of these animals were also viremic. Implants of human thymus or connective tissue, as well as the endogenous murine hematolymphoid organs, were not infected. As demonstrated by a combination of in situ hybridization and immunohistochemistry, both T-lymphoid and myelomonocytic lineage cells were infected in this system. HIV isolates that have been adapted to growth in vitro (e.g., HTLV-IIIb) were not infectious. When either 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxyinosine (ddIno) was administered to SCID-hu mice before HIV infection, the animals were protected in dose ranges similar to those used in man. This animal model may now be used as an efficient intermediate step between the lab and the clinic to study the infectious process in vivo and to best select efficacious antiviral compounds against HIV.

Ex vivo development of functional human lymph node and bronchus-associated lymphoid tissue

“…Indeed, this strategy allowed us, for the first time, to maintain a human lymph node long-term ex vivo. Although successful engraftment of human LNs in the SCID mouse host was reported by Kaneshima et al in 1991, 23 they later acknowledged that they were incapable of maintaining isolated human LNs for the long term because of the absence of adequate vascular and lymphatic connections, with surrounding (host) tissues held responsible for LN involution after 8 to 12 weeks. 24 Accordingly, we found that PLN maintenance in the SCID host (up to 36 weeks) was strictly dependent on the conservation of connective tissue attachments to the adjacent bronchial mucosa.…”

Simple i.v. Inoculation of HIV-1 to Thy/Liv SCID-hu Mice Induce Reproducible HIV Infection with Narrowing of Medulla in Human Thymic Implant.

“…In contrast to our findings, implanted thymus has been reported to be uninfected by i.v. inoculation of HIV-1 to the SCID-hu mice (10). It is possible that we used a different strain of HIV with relatively large amount of virus (10 5 TCID 50 ), which might have surmounted the rapid clearance of virus from the venous circulation by murine lung, liver and spleen [13].…”

“…SCID mice, 7 to 15 weeks of age, were implanted with human thymus and liver tissue from fetus of 17 gestational weeks, under the left kidney capsule. No infections of HIV to the fetal thymus were detected by repeated serological tests of anti-HIV antibody using the mother's sera for more than 3 months [10]. Human thymopoiesis was confirmed by flowcytometric analysis (see below) of the thymocytes The development of animal models of HIV infection and AIDS is essential for better understanding of the pathogenesis of HIV-induced immune deficiency and diseases, for testing new therapies involving candidate anti-HIV agents and for testing candidate vaccines.…”

“…Recently, several murine models for HIV infections have been developed by inoculating HIV-1 to various genetically immunodeficient inbred mice reconstituted with human hematolymphoid tissues [10,13,15,18]. Initially, human fetal thymus and liver implanted SCID mice (Thy/Liv SCIDhu mice) were constructed and were reported to provide both human hematopoietic progenitor cells and the stromal microenvironment in which T cell matures [18].…”

The Heptad Repeat 2 Domain Is a Major Determinant for Enhanced Human Immunodeficiency Virus Type 1 (HIV-1) Fusion and Pathogenicity of a Highly Pathogenic HIV-1 Env

“…Various models (both ex vivo and in vivo) have been utilized to study HIV-1-induced depletion of CD4 ϩ lymphocytes. Models such as SCID-human thymus-liver (SCID-hu thy/liv), tonsil histoculture, and human fetal thymus organ culture (HFTOC) have demonstrated significant use in the study of acute infection and pathogenesis in the appropriate lymphoid organ microenvironment as they retain the organ structure and do not require exogenous stimulation for productive viral infection to occur (2,20,28,32). More importantly, tissue culture-adapted HIV-1 isolates such as HXB2 fail to replicate in the SCID-hu thy/liv or HFTOC models (30,33).…”