Hiroaki Mitsuya

mitsuya hiroaki

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 outcome 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 and played a critical role in the discovery and development of the first three drugs for AIDS and HIV infection [zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC)]. Dr. Mitsuya has since been a leading researcher in the area of development of AIDS therapeutics and study of HIV resistance. Recently he has played a major role in the discovery and development of the next generation anti-HIV drug, darunavir.

In the therapy of HIV infection and AIDS, we have lately seen more than what is called cautious optimism. It is now evident that antiviral intervention brings about clinical benefits in both symptomatic and asymptomatic patients with HIV infection and that combined antriretroviral therapy blocks HIV replication more profoundly and persistently than ever and is capable of blocking HIV transmission from the infected to the uninfected.

In 1985, utilizing an in vitro drug testing system involving human target cells that Dr. Mitsuya created by 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 various 2',3'-dideoxynucleosides (ddNs) are active against HIV. Dr. Mitsuya also showed that ddNs serve as substrates for HIV reverse transcriptase and cause DNA chain termination in the reverse transcriptase-mediated proviral DNA synthesis and that ddNs become active against a number of human retroviruses under certain conditions, thus establishing the general conditions for the use of ddNs. Of such ddNs, ddI and ddC ultimately came into clinical use as important anti-HIV drugs. Since these epochal studies, Dr. Mitsuya has continued to produce important insights into the therapy of AIDS. In 1990s, Dr. Mitsuya showed for the first time that NRTIs can be classified into two groups: (i) 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 (ii) cell-activation-independent nucleoside reverse transcriptase inhibitors (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 antiretroviral therapy 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 have continued and extended the study of MDR HIV variants. 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 various PIs. One such PI is darunavir (DRV/TMC-114/Prezista), which was designed, synthesized and identified in collaboration with Professor Arun K. Ghosh of Purdue University.

DRV, unlike other PIs, binds to the main chains of the protease active site amino acids, a unique property, presumably enabling DRV to be active against multi-PI-resistant HIV variants. Most recently, Dr. Mitsuya and his group discovered that DRV and its related compounds strongly block the dimerization process of HIV protease, an essential process for HIV replication, using the FRET-based HIV expression system Dr. Mitsuya's group generated. Indeed, DRV, used with other drugs in combination, has been significantly benefiting a number of patients harboring multi-drug resistant HIV variants, whose clinical conditions would have been otherwise acutely deteriorating. DRV appears to have embodied a breakthrough in the struggle against the notorious obstacle of current AIDS therapy: multi-drug-resistant HIV variants. The dual antiviral function of DRV, inhibiting protease subunit dimerization as well as protease enzymatic activity, appears to explain why DRV is such a highly effective anti-AIDS therapeutic and differentiates itself from many of other "conventional" PIs. The development of DRV, the fourth AIDS drug developed at the NCI, was selected as one of the top two advances by the NCI in 2007 and this advance was sent to HHS for inclusion in the "Major Accomplishments by the NIH-2008".

Dr. Mitsuya is also developing a unique NRTI, 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA), which exerts highly potent antiviral activity against HIV-1, HIV-2, and simian immunodeficiency virus (SIV) with IC50 values of subnanomolar concentrations. EFdA has been shown to potently suppress SIV replication and increase CD4 T-cell counts in SIV-infected monkeys, in collaboration with Professor Michael Parniak of Pittsburgh University.

Dr. Mitsuya has been Chief, Experimental Retrovirology Section, NCI, USA since 1991; and Chairman and Professor, Departments of Hematology and Rheumatology, and Director, Division of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan since 1997. Dr. Mitsuya has also assumed a position of Director-General in the International Center for Clinical Research, National Center for Global Health and Medicine, Tokyo, Japan since January 2012.

Dr. Mitsuya has received various awards including NIH Director's Award (1992), First NIH World AIDS Day Award (2006), Medal with Purple Ribbon from Japan (2007), NCI HIV/AIDS Research Excellence Award (2007), Keio Medical Science Prize (2007) and Takamine Sankyo Memorial Award (2007). Dr. Mitsuya currently serves as Program Leader of a Global Center-of-Excellence Project in Japan (FY2008-): Global Education and Research Center Aiming at the Control of AIDS. Dr. Mitsuya has been Member of the American Society for Clinical Investigation (Young Turk, Elected in 1994) and Fellow of the American Academy of Microbiology (Elected in 2012).

 

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