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Updated: Feb 16, 2026
Chronic, Acute, and Reactivated HIV Infection in Humanized Immunodeficient Mouse Models
Published on: December 3, 2019
HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that
George N Llewellyn1, David Alvarez-Carbonell2, Morgan Chateau1
1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Abstract:
Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.
Insights
Researchers developed a humanized mouse model to study HIV latency in the brain. Phenelzine activated HIV production in human microglial cells, showing promise for targeting the central nervous system reservoir.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- The brain harbors a distinct HIV reservoir in glial cells, challenging traditional T cell focus.
- Studying brain HIV latency is difficult due to sample limitations and animal model constraints.
Purpose of the Study:
- To develop a small animal model for studying HIV latency in the brain.
- To identify compounds that can reverse HIV latency in microglial cells.
Main Methods:
- Humanized NSG mice were created by transplanting human hematopoietic stem cells.
- HIV infection was established, and virus presence in human microglia was confirmed.
- The CoREST complex's role in microglial HIV latency was investigated.
- Phenelzine's effect on HIV production in microglial cells was evaluated.
Main Results:
- Bone marrow-derived human microglia were successfully generated in the brains of humanized mice.
- HIV was detected in these microglia after infection.
- Phenelzine stimulated HIV production in both cell lines and cells from humanized mouse brains.
Conclusions:
- The developed humanized mouse model is a promising system for studying HIV latency in the CNS.
- Targeting CoREST repressors, like with phenelzine, may help reactivate the latent HIV reservoir in the brain.
- This model facilitates the development of strategies to reduce the central nervous system HIV reservoir.
