Humanized Mice for the Evaluation of Novel HIV-1 Therapies

Abstract

With the discovery of antiretroviral therapy, HIV-1 infection has transitioned into a manageable but chronic illness, which requires lifelong treatment. Nevertheless, complete eradication of the virus has still eluded us. This is partly due to the virus’s ability to remain in a dormant state in tissue reservoirs, ‘hidden’ from the host’s immune system. Also, the high mutation rate of HIV-1 results in escape mutations in response to many therapeutics. Regardless, the development of novel cures for HIV-1 continues to move forward with a range of approaches from immunotherapy to gene editing. However, to evaluate in vivo pathogenesis and the efficacy and safety of therapeutic approaches, a suitable animal model is necessary. To this end, the humanized mouse was developed by McCune in 1988 and has continued to be improved on over the past 30 years. Here, we review the variety of humanized mouse models that have been utilized through the years and describe their specific contribution in translating HIV-1 cure strategies to the clinic.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…Because HIV-1 elite controllers represent a minor portion of PLWH, it would be beneficial to establish animal models such as humanized mice and SIV-infected NHP with immune responses that mirror those of elite controllers. In the humanized mouse model, the immune system is reconstituted with human immune cells ( 79 ). Whereas mice are not susceptible to HIV-1 infection, numerous groups confirmed that HIV-1 can replicate in various humanized mice models ( 80 – 83 ), which are widely used to examine promising immunotherapies ( 84 ), latency reversing agents ( 85 ), and gene-editing of HIV-1 proviruses in vivo ( 86 , 87 ).…”

“…Although mice reconstituted with HLA-B*57 positive cells demonstrated better control of HIV-1 replication, they could not suppress HIV-1 replication to the point where viral loads would be lower than the limit of detection, in contrast to human ECs. It is important to note that their humanized mice model poorly reconstitute innate immune cells ( 79 ), and robust CD8+ T cell responses have been positively associated with more successful reconstitution of monocytes in humanized mouse models ( 91 ). Therefore, one possible explanation for why humanized mice could not achieve HIV-1 control is that EC innate immune responses were not recapitulated in their model.…”

The BCL-2 Inhibitor Venetoclax Augments Immune Effector Function Mediated by Fas Ligand, TRAIL, and Perforin/Granzyme B, Resulting in Reduced Plasma Viremia and Decreased HIV Reservoir Size during Acute HIV Infection in a Humanized Mouse Model

“…NOD/Shi-scid/IL-2Rγnull (NSG) immune-deficient mice were engrafted with hematopoietic stem cells (CD34 + HSC) derived from 2 donors. The NSG-HSC mouse model is a well-established platform, widely used to investigate and validate the effects of anti-HIV therapies, possessing a fully differentiated human immune system that can support HIV replication and reservoir establishment, and reconstituting intact innate immunity capable of response ( 66 , 67 ).…”

Using 2D and 3D pluripotent stem cell models to study neurotropic viruses

“…Human PSC-derived hematopoietic progenitors and microglia have been transplanted to the rodent brain and upon engraftment, these cells can acquire molecular properties that are more representative of in vivo populations than is typically observed in vitro ( 192 – 194 ). Similar strategies have been used to “humanize” animals that are otherwise resistant to infection of some viruses, such as HIV ( 195 ). Transplantation of human progenitors early in development can also facilitate investigations of viral pathogenesis in the developing brain.…”