From: Benefits and limitations of humanized mice in HIV persistence studies
Benefits | Limitations |
---|---|
In vivo model | Small animal size limits sample volumes and cell numbers that can be obtained |
– Recapitulates complexities not possible with in vitro systems | – Bleeds during experiment are restricted to several hundred microliter volumes |
– Allows experimental interventions and sampling not feasible in clinical studies | – Rare cell subsets such as latently-infected resting CD4+ T cells may require pooling of tissues for analysis in some tissues |
Supports robust infection with wild-type HIV | Nature of xenograft may interfere with some experimental approaches |
– Virus used for infection does not require genetic modification to overcome host species barriers | – Most tissues outside of the reconstituted human immune system are murine |
– Routes of infection are the same as in humans (allowing transmission or reservoir establishment studies) | – Graft-versus-host disease may develop and restrict timescale of experiments (time to GVHD is dependent on host strain and experimental model) |
– Clinically relevant antiretroviral drug regimens can be directly tested | |
– Reagents such as unmodified HIV-specific broadly neutralizing antibodies can be evaluated | |
Contains human HIV target cell types | Limited lifespan of mice |
– All major HIV host cell types are present, including CD4+ T cells and macrophages | – Depending on model, experiments lasting over 1 year are often infeasible |
– Infection causes CD4+ T cell depletion and other HIV-related immune defects, allowing mechanisms of HIV persistence and pathogenesis to be investigated | – HIV reservoir changes occurring only over long periods of time would likely not be captured in these models |
Forms latent HIV reservoirs in CD4+ T cells | Mice are individually humanized by transplantation of human cells and/or tissues |
– Allows testing of latency reversing agents | – Most advanced models require surgical techniques |
– Viral rebound occurs if ART is stopped | – Requires sources of human hematopoietic stem cells |
Reconstituted with human immune cytotoxic cells | Restrictions on the use of fetal tissues |
– Efforts to augment HIV-infected cell killing through natural killer cells or CD8+ T cells can be evaluated | – Models requiring implantation of human fetal tissues or cells are subject to substantial restrictions in some parts of the world |
Allows testing of human-specific gene or cytokine therapy approaches | Some immune cell lineage reconstitution and immune responses are incomplete |
– Gene therapy approaches specific for human genes can be directly evaluated (tailoring sequences to animal models for preclinical evaluation is not required) | – While newer models are improving this deficit, adaptive immune responses including IgG production and cytotoxic T cell responses have historically been difficult to elicit |
– Human specific cytokines can be evaluated for effects on human cells in vivo without species-related receptor-ligand incompatibilities | – Reconstitution with macrophage and natural killer cells is limited |
Permits large “N” to discern differences in experimental groups | Murine metabolism differs from human |
– >30 animals can be constructed in a single series from the same human donor cells/tissue | – Pharmacokinetic characteristics and drug metabolism in mice and human are different |
– Small animal size allows small amounts of experimental drug and compound to be used in pilot studies versus larger animal models |