Global COE Program Global Education and Research Center Aiming at the control of AIDS

Program Overview > Program Members > Seiji, Okada

Center for AIDS Research, Professor
Hematology, M.D., Ph.D. Research on Animal Model

Human Immunodeficiency Virus type 1 (HIV-1) is known to infect a variety of blood cells and influence the human immune and hematopoietic systems. Progress in the anti-HIV-1 therapy so called highly active antiretroviral therapy (HAART) has been successful in controlling HIV-1 infection and drastically improved the prognosis of HIV-1 patients. However, HAART cannot eliminate HIV-1 completely and even well controlled patients still have defects in immune system, which cause the AIDS-related malignancies. As the immune and hematopoietic systems are complex of diverse system, the analysis of the interaction between HIV-1 and these systems are crucial. In this program, we are going to clarify the interaction using in vitro culture system and mouse model especially focused on innate immunity (natural killer cells and macrophages) and hematopoietic stem cells. The goal of our study is to establish the control of HIV-1 infection by immune system.

1. Application of severe immunodeficient mice for AIDS research

As HIV-1 infection is complex biological process, animal model is the powerful tool to understand the AIDS pathology. Several attempts are performed to establish the mice with human immune system for 20 years. We developed the new generation of immunodeficient mice which accept the human tissues and generate human immune and hematopoietic systems, and established the three types of model mice. 1) Mice with long-term human immune and hematopoietic system (Humanized mice). 2) Mice with short term human immune system. 3) Mice with functional human NK cell expansion system. These mice provide an opportunity to study the pathogenesis of HIV-1 infection and to develop the new anti-HIV-1 drug and to test the potential vaccine.
With the recent advance of anti-HIV-1 drug therapy, the rate of opportunistic infection is decreased but HIV-associated malignancies are still remaining. Especially, AIDS related malignant lymphoma is now one of the leading causes of death among HIV-1 patients¹). We established the AIDS related lymphoma (ARL) model mice by transplant the lymphoma cell lines into the immunodeficient mice. These mice are the powerful tools to study the nature of AIDS related lymphoma (ARL) and to establish the new therapy for ARL. We are now focus on the establishment of the target therapy model: 1) Radioimmunotherapy using radioisotope (I-131, I-125, etc) conjugated monoclonal antibodies. 2) Cell therapy using NK cells and monoclonal antibodies. 3) Targeting therapy for NF-kB. Further more, we try to clarify the mechanisms of ARL development using the mice system, which is lead to the prevention of ARL.

2. Hematopoietic stem cells and HIV-1 infection.

HIV-1 infection alters hematopoiesis and HIV-1 patients often suffers form anemia and thrombocytopenia as well as lymphopenia. It is known that progenitor populations of magakaryocytes, monocytes and T lmphocytes are HIV-1 infectable. However, effects of HIV-1 infection on primitive hematopoeitic stem cells are still controversial. We are going to establish the system which mimic the hematopoiesis and HIV-1 interaction in combination with humanized mice and long-term culture system. Hematopoietic stem cell has self-renewal capacity and multipotentiality including produce T lymphocytes and macrophages, and it has potential to be transduced with pseudotyped lentivirus, indicating genetic modification of hematopoietic stem cells leads to protect cells from HIV-1 infection. Thus, we are going to establish

3. Innate Immunity and HIV-1 infection.

Natural killer (NK) cells and macrophages play important role for protection from viral infection and are also infected with HIV-1. HIV-1 infection alters the patients' innate immunity as well as adoptive immunity. Investigation of mechanisms to alter the NK and macrophage function enables us to finds out the effective cell therapy to control HIV-1 infection. We have already established the in vitro HIV-1 infection system to the NK cells²) and human NK cell expansion system in the immunodeficient mice³). These systems are very useful to figure out the NK cell HIV-1 interaction and develop the novel cell therapy using NK cells. NK cells have the antibody-dependent cell mediated cytotoxicity (ADCC) as a consequence of antibody being bound to a target cells surface via specific antigenic determinants expressed by the target cells (HIV-1 infected cells), besides cytokine production and direct cell killing (natural killer activity). We are now trying to develop the ADCC mediated anti-HIV-1 therapy using model mice. We are also targeting the NKT cells and macrophages for therapeutic use

♦Reference
1.	Nagai H, Iwasaki N, Odawara T, and Okada S; Actual status of AIDS-related lymphoma management in Japan. *Int J Hematol* 87(5):442-443, 2008
2.	Harada H, Goto Y, Ohno T, Suzu, S, and Okada S; Proliferative activation up-regulates the expression of HIV-1 receptors on NK cells and induces HIV-1 infection of NK cells. *Eur J Immunol* 37(8): 2148-2155, 2007
3.	Harada H, Suzu S, Ito T, and Okada S; Selective expansion and engraftment of human CD16⁺ NK cells in NOD/Scid mice. *Eur J Immunol* 35(12):3599-3609, 2005