The landscape of HIV (Human Immunodeficiency Virus) research has been an evolving one, with remarkable strides made over the past decades. However, the quest for a definitive cure for HIV infection and AIDS remains. Preclinical research plays a critical role in this journey, providing the foundation for the development of novel therapeutics and prevention strategies. Today’s preclinical HIV research is an exciting blend of exploratory studies and translational science. A significant focus is on the “shock and kill” strategy, aiming to eliminate HIV reservoirs. Moreover, advancements in antiretroviral therapy (ART) have transformed HIV into a manageable chronic condition, but the hunt for an elusive cure continues.
Animal models have long served as a fundamental component in preclinical research, contributing significantly to our understanding of HIV-1 transmission and treatment in humans. These insights have primarily been derived from studies conducted on non-human primate (NHP) models. However, a significant scientific limitation with these models is the inability of NHPs to be infected with HIV, necessitating the use of simian immunodeficiency virus (SIV) for data generation.
Both SIV and HIV are lentiviruses, a retrovirus subgroup known for causing lifelong infections in their hosts. The viruses share commonalities in genome structure, replication processes, and the capability to induce immunodeficiency diseases in their respective hosts. Despite these similarities, they exhibit key differences. While most NHPs infected with species-specific SIV do not develop AIDS, even with high virus replication levels, humans with untreated HIV infections typically progress to AIDS. The rate of genetic variability is another distinguishing factor, with HIV demonstrating a higher rate than SIV. This significant variability, resulting from errors made by the virus’s reverse transcriptase enzyme during replication, adds complexity to the creation of an effective HIV vaccine.
Beyond these crucial scientific differences, ethical and financial concerns emphasize the urgent need for alternative models. The US Department of Agriculture (USDA) estimates that approximately 70,000 monkeys were used solely for preclinical research in the USA. Rhesus macaques are in growing demand, primarily for research into HIV, the brain, Alzheimer’s disease, and addiction. Public opposition to animal research is also on the rise, with a 2017 Pew Research Center poll showing that 52% of Americans are against such studies. In addition, importing monkeys to the US has become increasingly challenging due to most commercial air carriers refusing to transport these animals.
For these reasons and others, non-human primate research has come under increasing scrutiny. For example, Harvard University closed its national primate research center in 2015 following a federal investigation into the deaths of four of its animals. That same year, NIH ceased its support of all invasive chimpanzee studies, drawing from a report that deemed such animals no longer essential to biomedical research. Moreover, in 2016, Congress directed NIH to hold a workshop discussing the utility and ethics of monkey research.
TransCure bioServices is uniquely positioned in this landscape as the only worldwide CRO offering an HIV model in humanized mice, a vital contribution to HIV preclinical research. As an AAALAC-accredited organization equipped with a BSL3 animal facility, TransCure is well-prepared to undertake advanced research on infectious agents such as HIV.
The unique features of the humanized mice model:
Due to the limited tropism of HIV for human T Cells, alternative animal models have been developed that support HIV replication and mimic key aspects of HIV infection and pathogenesis in humans. Humanized mice (HIS) are emerging as an alternative model system for studying HIV biology and pathogenesis.
In brief, highly immunodeficient mice are transplanted with CD34+ hematopoietic stem cells from umbilical cord blood. Complete hematopoiesis is fully recapitulated, and 14 weeks after CD34+ engraftment, a fully functional human immune system is established. These mice develop a complete and functional human immune system from T cells, B cells, Dendritic cells to monocyte and NK cells. Furthermore, contrary to PBMC engrafted mice, all mouse tissues in CD34 humanized mice are infiltrated (spleen, liver, bone marrow, lung…). Another advantage is the lifelong stability of the human immune system allowing longer studies with multiple cycle of treatments and wash-out.
This model provides a rapid, reliable, and reproducible experimental systems for HIV research. They offer an opportunity to assess HIV replication over time, allowing the evaluation of multiple parameters of infection such as rebound, latency and resistance.
The small size and cost of these models, the ability to make multiple cohorts from multiple human donors, and the continuous de novo production of human immune cells from transplanted CD34+ cells are among the advantages that make humanized mice a powerful tool in HIV research. Humanized mice hold a crucial role in virtually all aspects of HIV research, from analyzing HIV replication, understanding the reservoir, characterizing successful HIV prevention strategies, to evaluating new treatment regimens and novel HIV eradication strategies. TransCure bioServices is proud to lead the way in offering this model to the HIV research community, facilitating breakthroughs in HIV therapeutics and prevention.
CD34+ humanized mice represent an innovative tool in HIV preclinical research, offering both an ethical and economical alternative to primate models. Their use could potentially accelerate the pace of discovery in the relentless pursuit of an HIV cure.
In addition to the many scientific benefits of utilizing humanized mice in HIV research, the use of these models also aligns with the ethical 3R principles—Replacement, Reduction, and Refinement—of animal research. In terms of refinement, humanized mice offer a more ethical alternative to non-human primates for preclinical research. Non-human primates are phylogenetically closer to humans, resulting in a higher level of consciousness and a greater capacity to experience distress, making the use of humanized mice a less ethically challenging choice. Furthermore, humanized mice models provide an opportunity to refine experimental techniques and minimize animal suffering while maintaining the scientific rigor required for HIV research. By adhering to these ethical guidelines and prioritizing animal welfare, TransCure bioServices (accredited AAALAC in 2022) can continue to advance the understanding of HIV while upholding the highest ethical standards.
With these cutting-edge models at our disposal, the future of preclinical HIV research appears promising. The hope is that the use of CD34+ humanized mice will bring us closer to understanding HIV and developing a definitive cure. As researchers, we stand on the brink of exciting possibilities, eagerly anticipating the breakthroughs that lie ahead.
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Marsden MD, Zack JA. Humanized Mouse Models for Human Immunodeficiency Virus Infection. Annu Rev Virol. 2017 Sep 29;4(1):393-412. doi: 10.1146/annurev-virology-101416-041703. Epub 2017 Jul 26. PMID: 28746819; PMCID: PMC6542458.