The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

Abstract

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies.

FELASA recommendations for the health monitoring of mouse, rat, hamster, guinea pig and rabbit colonies in breeding and experimental units

“…These animals not only accept grafts but may also amplify microorganisms of human origin such as human immunodeficiency virus (HIV). 14 Human cell lines that are intended for use in animals should be screened for both rodent and human pathogens.…”

Generation of an HIV-1-Resistant Immune System with CD34 + Hematopoietic Stem Cells Transduced with a Triple-Combination Anti-HIV Lentiviral Vector

“…Three months after transplantation, functional human T cells, B cells, and macrophages can be detected in lymphoid organs, including the spleen, thymus, and bone marrow (6). Mice successfully engrafted with a human immune system can be infected with HIV and display normal HIV disease characteristics, including CD4…”

“…ϩ cell depletion and an increase in plasma viremia (6). This mouse model offers a unique preclinical in vivo system to evaluate anti-HIV gene therapy molecules in human cells at a level acceptable to regulatory agencies.…”

“…For the preclinical analysis of anti-HIV genes and vectors, it is necessary to utilize an appropriate in vivo model capable of demonstrating safety and efficacy of the novel therapy (6,8). The…”

Host Specificity of Bacterial Pathogens

“…Although studies of infection in humanized mice have only recently begun, this approach promises to provide unprecedented insights into mechanisms of host interaction with human pathogens including hepatitis viruses, HIV, CMV, EpsteinBarr virus, dengue virus, N. meningitidis, and Plasmodium falciparum (e.g., Bente 2005;Jimé-nez-Díaz 2009;Smith et al 2010;Berges and Rowan 2011;Sato et al 2011;Zeisel et al 2011;Melican et al 2013).…”