Our Science – Mitsuya Website

Hiroaki Mitsuya, M.D., Ph.D.

HIV and AIDS Malignancy Branch Head, Experimental Retrovirology Section Adjunct Investigator Building 10, Room 5A11 NCI-Bethesda Bethesda, MD 20892 Phone:   301-402-3631 Fax:   301-402-0709 E-Mail:   hmitsuya@helix.nih.gov

Biography

Dr. Hiroaki Mitsuya obtained his M.D. and Ph.D. in Kumamoto University School of Medicine in Japan. After receiving immunology/hematology/oncology training at Kumamoto University Hospital, Dr. Mitsuya joined the National Cancer Institute in 1982 and began studying the outcomes of infection by human T cell leukemia virus type 1, the first known human pathogenic retrovirus. In 1984, Dr. Mitsuya steered his attention to human immunodeficiency virus or HIV. In 1985, he identified three nucleoside reverse transcriptase inhibitors (NRTIs: 3'-azido-2',3'-dideoxythymidine or AZT, 2',3'-dideoxyinosine or ddI, and 2',3'-dideoxycytidine or ddC) now widely used in the treatment of acquired immunodeficiency syndrome (AIDS), and guided much of their preclinical development. Dr. Mitsuya has been chief of the Experimental Retrovirology Section since 1991.

Research

Development of Therapies for HIV Infection

In the therapy of HIV infection and AIDS, we have lately seen what is called cautious optimism. It is now evident that an antiviral intervention brings about clinical benefits in both symptomatic and asymptomatic patients and that protease inhibitors (PIs) administered with NRTIs block HIV replication more profoundly and persistently than ever. This significant progress was possible mainly in combination with NRTIs and PIs or highly active antiretroviral therapy (HAART). In 1985, utilizing an in vitro drug testing system involving human target cells Dr. Mitsuya created himself, he showed for the first time that AZT had potent anti-HIV activity in vitro. Based on his data, AZT was ultimately selected for the clinical trial at the NCI and he collaborated in a series of clinical studies establishing AZT as the first drug for AIDS therapy. Concomitantly, Dr. Mitsuya discovered that other 2',3'-dideoxynucleosides (ddNs) were also active against HIV in vitro. Of these, ddI and ddC ultimately came into clinical use as important anti-HIV drugs. Dr. Mitsuya also showed that ddNs served as substrates for HIV reverse transcriptase, which upon interaction with the latter undergoes viral DNA chain termination, and the ddNs are active against a number of human retroviruses under certain conditions, thus establishing the general conditions for the antiretroviral effect of ddNs.

Since these epochal studies, Dr. Mitsuya has continued to produce important insights into the potential therapy of AIDS. In 1993 to 1994, Dr. Mitsuya showed for the first time that NRTIs can be classified into two groups: (1) cell-activation-dependent ddNs such as AZT and 2',3'dideoxy-2',3'-didehydrothymidine (d4T) that are preferentially phosphorylated, yield higher ratios of ddN 5'-triphosphate (ddNTP)/2'-deoxynucleoside 5'-triphosphate (dNTP), and exert more potent anti-HIV activity in activated cells than in resting cells; and (2) cell-activation-independent NRTIs including ddI, and ddC that produce higher ratios of ddNTP/dNTP and exert more potent activity against the virus in resting cells. These findings have provided the basis for the design of currently available combination chemotherapy with NRTIs.

Another major focus of Dr. Mitsuya's research is the drug-resistant HIV problem. In 1992, Dr. Mitsuya showed that HIV develops resistance to AZT more readily than ddI and ddC and that HIV develops a set of novel mutations which confer multidrug resistance (MDR) on HIV. Dr. Mitsuya and his group has continued and extended the study of MDR HIV variants. The MDR-conferring mutations have been identified in 6 of 36 patients (approximately 20 percent) receiving combination chemotherapy in Dr. Mitsuya's study. A number of groups in the United States and Europe have increasingly confirmed that the emergence of MDR-HIV is an alarming problem in the therapy of HIV infection and prompt measures need to be taken to address this issue.

In response to the drug-resistant HIV problems and in collaboration with intramural and extramural scientists, Dr. Mitsuya's group has identified several promising protease inhibitors (PIs) which are extremely potent against wild-type HIV and HIV variants resistant to currently available PIs. One such PI, JE-2147 (AG-1776), has a flexible component that may be related to its anti-HIV activity against a wide spectrum of multi-PI-resistant variants. Another extremely potent novel PI is UIC-94017 (TMC-114) that, unlike other PIs, binds to the main chains of the protease active site amino acids, a unique property presumably enabling UIC-94017 (TMC-114) to be active against multi-PI-resistant HIV variants. Dr. Mitsuya has most recently identified novel CCR5 antagonistic spirodiketopiperazine derivatives (e.g., E913 and AK602/ON4128/GW873140) that are extremely potent against macrophage-tropic R5-HIV. Dr. Mitsuya and his group have a wide range of scientific and practical interests in a number of modalities of antiretroviral intervention and both national and international active collaborations are always in progress.

We have collaborated with Edward Arnold, Rutgers University; Arun Ghosh, University of Illinois at Chicago; Victor Marquez and Robert Yarchoan, NIH; Masao Matsuoka, Kyoto University, Kyoto, Japan; Shiro Shibayama of Ono Pharmaceutical Co., Ltd, Japan; and Jiri Zemlicka, Karmanos Cancer Institute, Detroit, MI.

This page was last updated on 6/12/2008.