A team led by researchers from Weill Cornell Medicine and Children’s National Hospital has developed a unique preclinical model that enables the study of long-term HIV infection and the testing of new therapies to cure the disease.
Ordinary mice cannot be infected with HIV, so previous HIV mouse models have used mice that carry human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. However, these models are generally only of limited use, as the human cells soon perceive the tissue of their mouse hosts as “foreign” and attack them, making the mice seriously ill.
In contrast, the new mouse model described in an article in the Journal of Experimental Medicine avoids this problem on May 14th by using a subset of human CD4 cells that largely excludes the cells that would attack mouse tissues. The researchers showed that the mice can usefully model the dynamics of long-term HIV infection, including the virus’ response to experimental therapies.
“We expect this to be a valuable and widely used tool to study the fundamentals of HIV infection and accelerate the development of better therapies,” said co-first author Dr. Chase McCann. During the study, Dr. McCann Weill Cornell Graduate School student in lead author Dr. Brad Jones, Associate Professor of Immunology in Medicine in the Infectious Diseases Department at Weill Cornell Medicine. Dr. McCann, who received a TL1 education award from the Clinical and Translational Science Center (CTSC) at Weill Cornell, is now director of the cell therapy laboratory at the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, DC. The other co-first authors of the study are Dr. Christiaan van Dorp from Los Alamos National Laboratory and Dr. Ali Danesh, a senior research scientist 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 for HIV infection. Cell therapies, such as those that use patient-developed T cells, are becoming increasingly popular in cancer treatment and have had some notable results. Many researchers hope that a similar strategy against HIV can work and possibly be curative. However, the lack of good mouse models has hampered the development of such therapies.
Drs. Jones and McCann and their colleagues showed in the study that the problem of the host cell attack found in earlier mouse models is mainly due to so-called “naive” CD4 cells. These are CD4 cells that have not yet been targeted and appear to contain a population of cells that can attack various mouse proteins. When the researchers excluded naive CD4 cells and instead used only “memory” CD4 cells, which circulate in the blood as sentinels to infection after exposure to a particular pathogen, the cells in the mice survived indefinitely without seriously harming their hosts.
The researchers observed that the human CD4 cells could also be infected and killed by HIV or protected by standard anti-HIV drugs, in much the same way as humans. In doing so, they showed that the mice they referred to as “participant-derived xenografts” or PDX mice served as a viable model for long-term HIV infection. This term is similar to the PDX “patient-derived xenograft” models used to study cancer therapies while recognizing the contributions of people living with HIV as active participants in the research.
Eventually, the researchers used the new model to investigate a prospective new T-cell-based therapy very similar to the one currently being tested against cancer. They inserted memory CD4 T cells from a human donor into the mice to allow HIV infection and then, after infection was detected, treated the mice with another infusion of human T cells, with they were CD8-type T cells, also known as “killer T” cells. “
The killer T cells came from the same human donor and were able to recognize a structure susceptible to HIV – so they attacked the virus wherever they found it in the mice. To make the killer T cells more effective, the researchers charged them with a T cell stimulating protein called IL-15.
The treatment greatly suppressed HIV in the mice. And although, as is often observed in human cases, the virus ultimately evolved to elude detection by the killer T cells, the simple use of the mouse model enabled researchers to monitor and control these long-term infection and virus escape dynamics in detail examine.
“I think the main effect of this model will be to accelerate the development of T-cell-based therapies that can overcome this virus escape problem,” said Dr. Jones.
He and his laboratory continue to study such therapies using the new mouse model with engineered T cells from Dr. McCann’s lab and others.