The Last Stop Before Starting Eradication Trials in Humans?
The entire dynamics of HIV transmission and disease progression in humans are extremely complex and cannot be replicated in vitro. HIV has genetic and biological differences with SIV and SHIV used in non human primate models. Humanized mice models of HIV infection have the advantages of recapitulating key aspects of HIV disease and being more widely affordable.
In a recent very detailed review, Denton and al (1) describe the potential contribution of humanized mice models of HIV infection to test new therapeutic strategies aimed at preventing or curing HIV infection.
Although non human SIV and SHIV primate models have contributed greatly to our understanding of HIV infection, their numbers are limited and their cost is another limitation to their use.
The term "humanized mice" has been applied to a variety of mouse models:
-mice that have single or multiple human transgene(s) in an otherwise wild-type animal
-immunodeficient mice transplanted with human cells or implanted with normal or diseased human tissues
-CD34+ hematopoietic progenitor cell engrafted immunodeficient mice
-and various combinations of these previous situations.
Whereas most lymphoid cells develop in the bone marrow, T-cells do not. Thymic progenitors exit the bone marrow and migrate to the thymus because T-cells require the microenvironment present in this organ to develop.
In CD34+ transplanted mice this takes place in the mouse thymus, although in bone marrow liver thymus (BLT) mice it takes place in an implanted human thymus. Consequently, in BLT mice T cells are educated in the context of HLA.
Although humanized mice models have great advantages like not using a surrogate virus but HIV itself, they also have limitations. One is their relatively shorter half-life compared to non human primates and humans.
Three strains of immunodeficient mice are usually used to generate humanized mice:
-nonobese diabetic/SCID (NOD/SCID)
To generate CD34+ cell transplanted humanized mice, individual mice are preconditionned (gamma irradiation or busulfan) to create a niche in the bone marrow for the transplanted human CD34+ hematopoietic progenitor cells. Human CD34+ cells for transplantation are derived from umbilical cord blood, fetal liver, or G-CSF mobilized peripheral blood.
In the case of humanized BLT mice, each animal receives both transplanted CD34+ cells and implanted tissues from the same donnor.
Regardless of the source of the CD34+ cells, engraftment with hematopoietic progenitor cells results in a life-long supply of human immune cells in transplanted humanized mice.
Human immune cells, including T, B, NK, myeloid, and dendritic cells are found throughout BLT mice. In BLT mice, both the intraepithelial and lamina propria compartments of the small and large intestines are populated with human T lymphocytes. The BLT mouse female reproductive tract is also well reconstituted with human immune cells.
In CD34+ cell transplant mice, human T cells are generated in the mouse thymus. Reconstitution of the intestines and female reproductive tracts has not been fully addressed in the literature compared to BLT mice. It is clear that human cells can migrate to the female reproductive tract and intestines of CD34+ cell transplanted mice, but the extend to which these human immune cells are able to reconstitute remains uncertain.
Multiple cohorts of these humanized mice models of HIV infection can be made from multiple human donnors and each cohort has identical human cells, permitting control of intragenic variables. Both primary and laboratory HIV isolates can be used. Rectal and vaginal HIV transmission can both be tested.
Therefore, these models appear to be very interesting both for the study of pre-exposure prophylaxis and novel eradication strategies.
Denton PW, Garcia JV. Humanized Mouse Models of HIV Infection. AIDS Rev 2011; 13: 135-48
Key words: HIV Elite Controllers, HIV animal models, HIV functional cure, humanized mouse