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Table 1 Broad benefits and limitations of humanized mouse models in HIV persistence research

From: Benefits and limitations of humanized mice in HIV persistence studies

BenefitsLimitations
In vivo modelSmall 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 HIVNature 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 typesLimited 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 cellsMice 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 cellsRestrictions 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 approachesSome 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 groupsMurine 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 
  1. Humanized mice are powerful tools for studying HIV persistence and latency. However, as for all model systems they are more suitable for addressing some questions than others as summarized here