One of the most prevalent uses of humanized mice is the study of human-specific infectious agents, particularly HIV [38
]. Using the SCID-hu system, robust virus-specific immune responses following HIV infection were observed [40*
]. Despite these robust responses, HIV viral load remained high and correlated with increased PD1 expression on human T cells, an observation also made in humans [41
]. In a model based on NOD-scid Jak3null
mice, a nucleoside reverse transcriptase inhibitor blocked HIV infection in Hu-PBL-SCID mice [44
]. Using the Hu-SRC-SCID model based on BALB/c-Rag1null IL2rynull
mice, in vivo
RNAi gene therapy against HIV-1 was investigated [45
]. Human HSC were transduced with a lentiviral vector expressing a shRNA against HIV-1 nef
gene and engrafted into newborn BALB/c-Rag1null IL2rynull
mice. Evidence was obtained that the mature human CD4 T cells recovered from the HSC-engrafted mice exhibited an inhibition of virus replication, confirming efficacy of the shRNA therapy.
In a key series of experiments using both the Hu-PBL-SCID and Hu-SRC-SCID models based on NOD-scid IL2rynull
mice, Kumar et al
validated a novel new drug for the prevention and treatment of HIV infection [46**
]. They used a modified single chain antibody (scFv) to the human T cell marker CD7 to deliver siRNA in vivo
against CCR5 and viral Vif
genes to human CD4 T cells in humanized mice. They documented that HIV infection could be controlled in a prophylactic setting in both model systems when viral challenge was performed after initiation of siRNA treatment, as well as in a post-infection setting, where mice were engrafted with PBMC from an HIV-infected subject.
A number of reports have described Dengue virus humanized mouse models for which no animal model system previously existed. Using newborn HSC-engrafted NOD-scid IL2rynull
mice infected with eight different viral strains representing the four genotypes of Dengue viruses, viremia, a thrombocytopenia, increase in body temperature and erythema were observed corresponding to clinical characteristics in Dengue-infected humans [47
Another approach in addition to the SCID-hu model to enhance human T cell selection during development in the thymus is to transgenically express human HLA in the mouse recipient. In a report using Hu-SRC-SCID mice based on NOD-scid IL2rynull
HLA-A2 transgenic mice engrafted with HLA-A2 HSC, Jaiswal et al
documented the development of virus-specific HLA-A2-restricted human T cell responses to Dengue virus infection [49*
]. This is one of the first two reports using HLA-transgenic mice to document a human T cell HLA-restricted immune response. The other report used Epstein Barr Virus (EBV) infection in a model also based on NOD-scid IL2rynull
HLA-A2 transgenic mice engrafted with HLA-A2 HSC [50**
]. HLA-A2-restricted cytotoxic and IFNy-producing human T cells against multiple EBV HLA-A2 epitopes were observed exhibiting similar patterns of reactivity to that detected in human EBV carriers. These two reports document that HLA expressed transgenically in mouse thymus can positively select developing T cells and lead to HLA-restricted immune responses in mice engrafted with human HSC. Development of additional HLA-transgenic immunodeficient mice is currently underway [2
mice engrafted as newborns with HSC were used to document a novel approach for enhancing immune responses following immunization. Targeting EBV antigen to human DC in vivo
stimulated human T cell responses to EBV and induced anti-EBV antibody responses [51
]. Similarly, NOD-scid
mice engrafted with human HSC and autologous mature T cells and then infected with live attenuated trivalent influenza virus generated human T cell responses to influenza [52
]. The authors proposed this as a model for investigating antigen-presenting cells in immune responses as the response was completely dependent on reconstitution of the human myeloid compartment.
Finally, the first humanized mouse model for the study of Plasmodium falciparum
was recently reported [53*
]. NOD-scid IL2rynull
mice were injected repeatedly with human red blood cells, which could then support productive infection with P. falciparum
. Therapeutic efficacy of a number of anti-malarial agents was tested, permitting determination of the protective ED90
of the drugs against infection.
Overall, infectious disease studies in humanized mice are providing important pre-clinical model systems for the investigation of the pathogenesis of human-specific infectious agents, evaluation of therapeutics, and platforms to understand mechanisms of human immune responses following vaccination.