A team led by researchers at Weill Cornell Medicine and Children’s National Hospital has developed a unique preclinical model that can study long-term HIV infection and test new therapies to cure the disease.
Normal mice cannot be infected with HIV, so previous HIV mouse models have used mice that contain human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models usually have limited utility because human cells quickly perceive and attack the tissues of their mouse hosts as ‘foreign’ – making the mice seriously ill.
In contrast, the new mouse model, described in a paper in the Journal of Experimental Medicine on May 14, 2021, avoids this problem by using a subset of human CD4 cells that typically exclude the cells that would attack mouse tissue. The researchers showed that the mice can usefully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies.
“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection and for accelerating the development of better therapies,” said co-first author Dr. Chase McCann. During the study, Dr. McCann a Weill Cornell Graduate School student in senior author Dr. Brad Jones, associate professor of immunology in medicine in Weill Cornell Medicine’s Division of Infectious Diseases. Dr. McCann, who was supported by a TL1 training award from the Clinical and Translational Science Center (CTSC) at Weill Cornell, is now the Lead of the Cell Therapy Lab at the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, DC. The other co-lead authors of the study are Dr. Christiaan van Dorp of Los Alamos National Laboratory and Dr. Ali Danesh, a senior research associate in medicine at Weill Cornell Medicine.
The invention of the new mouse model is part of a broader effort to develop and test cell therapies against HIV infection. Cell therapies, such as those that use the patient’s own engineered T cells, are increasingly common in the treatment of cancer and have shown remarkable results. Many researchers hope that a similar strategy can work against HIV and be potentially curative. But the lack of good mouse models has hindered the development of such therapies.
Drs. Jones and McCann and their colleagues showed in the study that the cell attack host problem found in previous mouse models is mainly due to so-called “naive” CD4 cells. These are CD4 cells that have not yet been exposed to targets, and apparently contain a population of cells that can attack various mouse proteins. When the researchers ruled out naive CD4 cells and instead used only “memory” CD4 cells, which circulate in the blood as guards against infection after exposure to a specific pathogen, the cells survived indefinitely in the mice without major damage to them. to cause their hosts.
The researchers noted that human CD4 cells can also be infected and killed by HIV, or protected by standard anti-HIV drugs, in essentially the same way as in humans. Thus, they showed that the mice, which they called “participant-derived xenograft” or PDX mice, served as a workable model for long-term HIV infection. This term is related to the PDX models of “patient-derived xenograft” used to study cancer therapies, while acknowledging the contributions of people with HIV as active participants in research.
Finally, the researchers used the new model to study a future new T-cell-based therapy, similar to one currently being tested against cancer. They put CD4 memory T cells from a human donor into the mice to allow HIV infection, and then, after the infection was diagnosed, they treated the mice with a new infusion of human T cells, which are CD8 -type T cells, also called ‘killer T cells’. cells. “
The deadly T cells were from the same human donor and could recognize a fragile structure on HIV – so they attacked the virus wherever they found it in the mice. To increase the effectiveness of the deadly T cells, the researchers supercharged them with a T cell stimulating protein called IL-15.
The treatment potently suppressed HIV in the mice. And although, as is often seen in humans, the virus eventually evolved to escape recognition by the deadly T cells, the ease of use of the mouse model allowed the researchers to track and monitor these long-term infection and viral escape dynamics in detail. to study.
“I think the main impact of this model will be to accelerate the development of T-cell-based therapies that can overcome this viral escape problem,” said Dr. Jones.
He and his lab are continuing to study such therapies using the new mouse model, using engineered T cells from Dr. McCann and others.
Reference: “A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies” by Chase D. McCann, Christiaan H. van Dorp, Ali Danesh, Adam R. Ward, Thomas R. Dilling, Talia M. Mota, Elizabeth Zale, Eva M. Stevenson, Shabnum Patel, Chanson J. Brumme, Winnie Dong, Douglas S. Jones, Thomas L. Andresen, Bruce D. Walker, Zabrina L. Brumme, Catherine M. Bollard, Alan S. Perelson, Darrell J. Irvine and R. Brad Jones, May 14, 2021, Journal of Experimental Medicine.
DOI: 10.1084 / jem.20201908