Developing a High Efficient Gene-Editing Tool to Edit the Human APOBEC3G Gene in HSC for Improving HIV-1 Treatment
Abstract
Our proposal will address one of the Fiscal Year 2019 Peer Reviewed Medical Research Program topics “Antimicrobial Resistance: Development of gene-editing tools (e.g., designer nucleases) that optimize treatment and raise the threshold for resistance to anti-infective agents.” Specifically, we propose to develop a tool to modify the human gene for the purpose of optimizing human immunodeficiency virus type 1 and acquired immune deficiency syndrome (HIV-1/AIDS) patient treatment and making HIV difficult to generate drug resistance. HIV/AIDS is continuing to be a global pandemic. As of 2017, approximately 36.9 million people are living with HIV globally. Approximately 940,000 deaths occurred from AIDS in 2017. Since the epidemic began in the early 1980s, 1.2 million people have been diagnosed with AIDS in the U.S., with 1.1 million people in 2014 living with HIV. One in seven of them are not aware of the disease presence, with an estimated 161,200 (13%) not having been diagnosed. In 2015, 39,513 people were diagnosed with HIV infection in the U.S. HIV infection is also a substantial health concern for the U.S. Department of Defense and for Service members stationed throughout the world. Each year, approximately 350 new HIV infections are diagnosed in members of the U.S. Armed Forces. In 2018, the Department of Veterans Affairs cared for over 31,000 Veterans with HIV. Despite these relatively low rates, these diagnoses lend to an appreciable impact on military missions and troop readiness due to the incurable nature of the infection, the need for lifelong therapy, the high cost of treatment, and limitations to duty assignments for HIV-infected Service members. It is urgent to develop a strategy to optimize the AIDS treatment to achieve persistent lifelong virologic suppression without the need for frequent treatments (e.g., HIV cure) and raise the threshold for resistance to anti-HIV drugs. The goal of this project is to develop an HIV-1 functional cure strategy by taking advantage of the strong anti-HIV function of the Apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G, or A3G). A3G is a human protein with strong activity to inhibit HIV-1 grow. However, under normal conditions, HIV finds a way to bypass A3G’s antiviral activity. People have found that when A3G protein is modified in a certain way, HIV will not be able to bypass A3G’s antiviral activity. In our recent study, we found that when we introduced the modified A3G to a human T cell line, we rendered the T cell line resistant to HIV infection over a very long period of time. This interesting data suggests a promising gene therapy strategy for optimizing AIDS treatment. We could introduce the modified A3G to the hematopoietic stem cells (HSCs), which are cells for making new blood cells, harvested from AIDS patients or donors. The modified HSCs will make new blood cells, such as CD4+ T cells, dendritic cells, and macrophages, etc. The new blood cells will inherit the modified A3G, and they will not support HIV growth in these blood cells. The non-modified stem cells in the patient’s bone marrow are ablated with chemotherapy or irradiation, which allows the genetically engineered HIV-resistant blood cells to grow. At a certain point, the blood cells in the patients’ bodies no long support HIV growth. The patient may no longer need anti-AIDS drug or may take drugs less often. This idea has never been tested before. It takes advantage of the cutting-edge technology of gene modification (CRISPR Cas9) and the unique antiviral feature of the modified A3G to develop an HIV cure strategy; therefore, our research is innovative. We expect to develop an efficient tool to modify human A3G gene in HSCs, and the T cells derived from the genetically modified HSCs will be resistant to HIV long-term infection. The results will lay a foundation for future testing of this hypothesis in an animal model, which could lead to a clinical trial.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010062
Entities
People
- Bindong Liu
Organizations
- Meharry Medical College
- United States Army